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Vitamin D and Cardiovascular Disease

Originally published17 Jan 2014https://doi.org/10.1161/CIRCRESAHA.113.301241Circulation Research. 2014;114:379–393

    Abstract

    Vitamin D plays a classical hormonal role in skeletal health by regulating calcium and phosphorus metabolism. Vitamin D metabolites also have physiological functions in nonskeletal tissues, where local synthesis influences regulatory pathways via paracrine and autocrine mechanisms. The active metabolite of vitamin D, 1α,25-dihydroxyvitamin D, binds to the vitamin D receptor that regulates numerous genes involved in fundamental processes of potential relevance to cardiovascular disease, including cell proliferation and differentiation, apoptosis, oxidative stress, membrane transport, matrix homeostasis, and cell adhesion. Vitamin D receptors have been found in all the major cardiovascular cell types including cardiomyocytes, arterial wall cells, and immune cells. Experimental studies have established a role for vitamin D metabolites in pathways that are integral to cardiovascular function and disease, including inflammation, thrombosis, and the renin–angiotensin system. Clinical studies have generally demonstrated an independent association between vitamin D deficiency and various manifestations of degenerative cardiovascular disease including vascular calcification. However, the role of vitamin D supplementation in the management of cardiovascular disease remains to be established. This review summarizes the clinical studies showing associations between vitamin D status and cardiovascular disease and the experimental studies that explore the mechanistic basis for these associations.

    Vitamin D Physiology and Metabolism

    Vitamin D (nutritional term for compounds with biological activity of 1α,25-dihydroxyvitamin D; also used to indicate summation of Vitamin D2 and D3) is a fat-soluble vitamin that functions as a steroid hormone. It plays a crucial role in mineral homeostasis and skeletal health and its deficiency classically leads to rickets in children and osteomalacia in adults.1 Its primary action on the skeletal system is to regulate calcium and phosphorus metabolism by influencing intestinal absorption, bone resorption, and renal retention (Figure 1). Vitamin D metabolites also play an integral physiological role in nonskeletal tissues and have been implicated in a wide range of chronic pathology, including skin and autoimmune disease, cancer, diabetes mellitus, hypertension, and cardiovascular disease (CVD).2 Interest in the role of vitamin D in CVD arose from evidence of adverse cardiovascular effects of vitamin D deficiency in animal models,3 and epidemiological studies reporting the increase in cardiovascular events in winter and at increasing distance from the equator.4,5

    Figure 1.

    Figure 1. Endocrine pathways of vitamin D metabolites. FGF-23 indicates fibroblast growth factor 23. Adapted from Holick1 with permission of the publisher. Copyright © 2007 Massachusetts Medical Society. Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.

    Vitamin D3 (cholecalciferol) is mainly produced nonenzymatically from precursors when skin is exposed to ultraviolet light. Skin synthesis of vitamin D3 is much more important than any dietary sources such as fatty fish. Vitamin D2 (ergocalciferol) is a plant-derived form of vitamin D manufactured through exposure of yeast to ultraviolet light.1 The inactive precursors (or prohormones) from either skin production or diet undergo 25-hydroxylation by 1 of 4 cytochrome P450 enzymes (most importantly CYP2R1) in the liver producing 25-hydroxyvitamin D [25(OH)D], the form usually considered as a circulating biomarker of vitamin D status. Subsequent conversion by 1α-hydroxylase (another cytochrome P450 enzyme; CYP27B1) into the active form, 1α,25-dihydroxyvitamin D [1,25(OH)2D] or calcitriol, occurs primarily in the kidney (Figure 1). Strict transcriptional feedback mechanisms involving parathyroid hormone and fibroblast growth factor 23 control renal production of 1,25(OH)2D, and all target cells express 24-hydroxylase that converts 1,25(OH)2D into an inactive form [1,24(OH)2D].6 Various extrarenal tissues, including many cell types involved in CVD, also express CYP27B1 and are therefore able to produce 1,25(OH)2D. This local production and breakdown is not subject to the same feedback controls as renal production.

    Vitamin D Deficiency and Excess

    There is controversy about the definition of vitamin D deficiency (or hypovitaminosis D), the optimum serum level of 25(OH)D, and the dietary requirements of vitamin D.7,8 The Endocrine Society Clinical Practice Guideline defines vitamin D deficiency as 25(OH)D level <50 nmol/L (20 ng/mL) and insufficiency as 52.5 to 72.5 nmol/L.9 The International Osteoporosis Foundation defines vitamin D deficiency as 25(OH)D level <25 nmol/L and insufficiency as <50 nmol/L, and a target level of 75 nmol/L.10 The Institute of Medicine11 recommends that a target level of 50 nmol/L is sufficient for bone health. This lack of consensus, along with inherent fluctuations with season, diet, and supplements, makes the assessment of the relationship between vitamin D status and CVD complex.2 The variability between the different assays used to measure serum 25(OH)D also aggravates the lack of consensus between guidelines.12 Furthermore, local vitamin D metabolite concentrations within the arterial wall may be different from circulating levels because vascular smooth muscle cells (VSMC), endothelial cells (ECs), macrophages, and dendritic cells all have CYP27B1 activity and can produce 1,25(OH)2D from 25(OH)D.13,14

    Twin and genetic studies have underscored the heritability of circulating 25(OH)D levels (estimated to be between 23% and 77%), and recent genome wide association studies have identified several genes in the biosynthetic and activation pathways of vitamin D that are associated with variation in serum concentrations. These studies also assessed genetic variability in the vitamin D receptor (VDR).15–17 The role of these variants in CVD remains to be established.

    Vitamin D deficiency is considered to be a global problem,18 with reduced skin synthesis attributable to aging and environmental factors being the most common cause.1 As with CVD, the prevalence of vitamin D deficiency varies considerably with sex, age, latitude, ethnicity, and culture but is >50% in many subgroups, particularly the elderly.18 The prevalence of vitamin D deficiency is high among individuals with CVD. For example, in the National Health and Nutrition Examination Survey (NHANES) 2001 to 2004, 68% of whites, 88% of Hispanics, and 97% of blacks with CVD had 25OHD levels <75 nmol/L (less than the International Osteoporosis Foundation recommended concentration).19

    The focus in recent decades has been on the risks of vitamin D deficiency. This is appropriate given the epidemiological evidence that deficiency is a major public health problem. However, excess vitamin D can have adverse effects (particularly with high calcium intake), such as kidney stones, renal impairment, malignancy, and possibly some manifestations of CVD.7

    Vitamin D Receptor

    VDR is a member of the nuclear receptor superfamily, and it regulates numerous genes whose promoters contain vitamin D response elements. These genes are involved in regulatory processes of potential relevance to CVD, including cell proliferation and differentiation, apoptosis, oxidative stress, membrane transport, matrix homeostasis, tissue mineralization, and cell adhesion.20 VDRs have been found in all the major cardiovascular cell types, including VSMC,21 EC,22 cardiomyocytes,23 most immune cells,24 and platelets.25

    VDR binds 1,25(OH)2D with high affinity and specificity and then heterodimerizes predominantly with retinoid X receptor (Figure 2). Structurally, VDR consists of a short N-terminal domain before the DNA-binding domain comprising 2 zinc fingers, the first conferring vitamin D response element specificity and the second providing a site for heterodimerization.2 The rest of the molecule contains the lipophilic 1,25(OH)2D-binding domain and at the C-terminal, the coactivator-binding domain.2 Gene expression is dependent on the involvement of tissue-specific coactivators, including steroid receptor coactivator, and the silencing of corepressors that modify chromatin structure thereby allowing gene transcription; the DNA-binding domain is small, and contact is limited to 6 nucleotides in the opened DNA groove.26 These protein complexes influence target gene specificity that may be of relevance in CVD; for example, mothers against decapentaplegic homolog 3 that is involved in transforming growth factor-β transcription also coactivates the VDR.27 VDR downregulates some genes, including those for parathyroid hormone and CYP27B1.20

    Figure 2.

    Figure 2. Cell membrane and genomic effects of the vitamin D receptor. Adapted with permission from Norman.26 Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation. MAP indicates mitogen-activated protein; PIP3, phosphatidylinositol (3,4,5)-triphosphate; RAF, proto-oncogene serine/threonine protein kinase; RXR, retinoid X receptor; and VDRE, vitamin D response elements.

    There has been some interest in epigenetic effects of vitamin D metabolites with emerging evidence that VDR activation can influence post-translational events via the generation of specific subsets of microRNAs.28 As with some other nuclear receptors, VDR displays rapid (seconds to minutes) nongenomic effects involving transmembrane calcium transport and various second messengers that may in turn modulate gene expression (Figure 2).26,29 Our understanding of the importance of this signaling concerning CVD is limited.26

    Mechanistic Basis of the Effect of 1,25(OH)2D on Cardiovascular Function

    Several pathways and cell types that are relevant to cardiovascular physiology and pathology are influenced by vitamin D metabolites as summarized in Figure 3 and the Table. Most cardiovascular and inflammatory cells express CYP27B1, enabling local synthesis of 1,25(OH)2D.53 This target cell synthesis of 1,25(OH)2D seems to be particularly important in the nonskeletal actions of vitamin D and may explain evidence, suggesting that serum concentration of 25(OH)D correlates better with clinical outcomes than 1,25(OH)2D concentration.69

    Figure 3.

    Figure 3. Overview of vitamin D receptor (VDR)–mediated endocrine actions of 1,25(OH)2D on arterial wall and cardiac cells. PAI-1 indicates plasminogen activator inhibitor-1; and RAS, renin–angiotensin system. (Illustration credit: Ben Smith.)

    Table. Autocrine and Paracrine 1,25(OH)2D Signaling in Cardiovascular Cells

    Cell TypeEffect on Gene Expression and Cell MetabolismFunctional OutcomeCardiovascular Significance
    EC↓ NFKB, ↓IL-6 expression30↓ Endothelial inflammation, improved flow–mediated dilation30↓ Atherosclerosis
    ↓ Ca2+ influx,33 ↑ NO production32
    ↓ AII-induced ROS generation33↓ Endothelium-dependent contraction; optimal blood pressure↓ Hypertension
    ↓ Cyclin-dependent kinase34↓ Proliferation, ↑ monocyte adhesion35Unclear relevance to atherosclerosis
    SMCp38 MAP kinase, p21,p38, Cdk234,36–38Modulation of proliferation and migration36,39,40↓ Atherosclerosis and ?intimal hyperplasia
    Altered expression of osteoblastic genes (alk phos, MGA, OP, ON, PTH-rP, Msx2, BMP2, Runx2, OC, Osterix)41–44Altered tissue mineralizationVariable dose-dependent influence of vascular calcification
    ↓ Elastin expression45?↓ Aortic elastin contentUnclear relevance to aneurysmal phenotype
    ↓ TF, ↓PAI-1, ↓ THSP1, ↑ TM)46Physiological balance of thrombosis and hemostasis↓ Thrombogenicity
    ↓ TGFβ expression41,47Matrix homeostasis↓ Aneurysmal phenotype
    ↓ Oxytocin receptor, ↑ type-B endothelin receptor expression41NO release, physiological vascular tone↓ Hypertension
    ↑ VEGF expression21,48Improved endothelial repair↓ Atherosclerotic plaque initiation
    ↑ CYP24A1Autoregulation of local 1,25(OH)2D productionPrevention of local 1,25(OH)2D toxicity
    Macrophage↓ bic expression and microRNA-155 production49↑ SOCS↓ Inflammation
    ↑ IL-4, IL-10↑ Anti-inflammatory↓ Atherosclerosis
    ↓ IL-6, IL-1, IL-23, TLR, TNFα, IFN-γ30,50–53↓ Proinflammatory gene expression
    ↓ TF, ↑ TM54Physiological balance of thrombosis and hemostasis↓ Thrombogenicity
    ↓ RAS activation, ↓ ER stress55,56↓ Cholesterol uptake and foam cell formation57↓ Atherosclerosis
    ↑ CYP24A1Autoregulation of local 1,25(OH)2D productionPrevention of local 1,25(OH)2D toxicity
    Dendritic cell↓ Proliferation and maturation24Induction of tolerogenic phenotype↓ Vulnerable atherosclerotic plaque
    ↓IL-12, ↑IL-1024↓ T cell stimulation58
    ↓ Inflammatory response? Effect on aneurysmal phenotype
    T cell↓TH1, ↓TH1, ↑TREG, ↑TH259Tolerogenic adaptive immune response↓ Atherosclerosis
    ↑ IL-5, ↑ IL-1024↓ Inflammatory response58
    Cardiomyocyte↑TIMP-1 and -2, ↓MMP-2 and -960Physiological matrix turnover and cardiac remodeling↓ Cardiac hypertrophy
    ↓c-myc expression, ↓RAS activation61,62? ↓ Heart failure
    ↓ANP, ↑ type 1 natiuretic peptide receptor A63,64↓ RAS,?↓ Proliferation/ventricular hypertrophy62,65,66
    Myosin expression, sarcomere function67,68Cardiac contractility62Optimal diastolic coronary perfusion
    Aortic valve fibroblastOsteogenic factors ↓BMP2↓ matrix calcification44↓ Valve calcification

    ANP indicates atrial natriuretic peptide; BMP2, bone morphogenetic protein 2; Cdk2, cyclin-dependent kinase 2; CYP24A1, 24-hydroxylase; EC, endothelial cell; IFN-γ, interferon-γ; IL, interleukin; MAP, mitogen-activated protein; MGA, matrix gla protein; MMP, matrix-metalloproteinase; NFκB, nuclear factor κB; OC, osteocalcin; ON, osteonectin; PAI-1, plasminogen activator inhibitor-1; PTH-rP, parathyroid-related protein; RAS, renin–angiotensin system; ROS, reactive oxygen species; SMC, smooth muscle cell; SOCS, suppressors of cytokine signaling; TF, tissue factor; TGF-β, transforming growth factor-β; TIMP-1, tissue inhibitor of matrix metalloproteinase-1; TLR, toll-like receptor; TM, thrombomodulin; TNF-α, tumor necrosis factor-α; and VEGF, vascular endothelial growth factor.

    Inflammation: Endocrine, Paracrine, and Autocrine Actions of Vitamin D Metabolites

    Immune and inflammatory cells play key roles in all forms of CVD including atherosclerosis.70 VDR has been identified in most immune cells, notably in macrophages, dendritic cells, and activated T cells. Overall, 1,25(OH)2D controls inflammatory and immune responses keeping them within physiological boundaries (Figure 3). Although early innate immune responses to infection are stimulated with enhanced cytokine release, this is tempered by negative feedback loops, and adaptive immune responses to 1,25(OH)2D are generally anti-inflammatory (Figure 4). Proinflammatory cytokines such as interleukin-1 (IL-1), IL-2, IL-6, IL-23, tumor necrosis factor-α, and interferon-γ are downregulated, and anti-inflammatory ones such as IL-4 and IL-10 are upregulated.50–52 Both 1,25(OH2)D and 25(OH)D inhibit the production of tumor necrosis factor-α and IL-6 by targeting monocyte/macrophage mitogen-activated protein kinase phosphatase-1.53 There is some evidence that epigenetic mechanisms may be involved in the attenuation of Toll-like receptor-mediated inflammation by 1,25(OH)2D; the suppressor of cytokine signaling 1 is stimulated by 1,25(OH)2D via downregulation of proinflammatory microRNA-155 production in macrophages (Figure 5).49 In patients with type 2 diabetes mellitus, endoplasmic reticulum stress and the uptake of cholesterol by macrophages is suppressed by 1,25(OH)2D, with reduced foam cell formation.56,57

    Figure 4.

    Figure 4. Vitamin D metabolites and immune modulation: endocrine, paracrine, and autocrine responses. IL indicates interleukin; INF-γ, interferon-γ; PGE2, prostaglandin E2; TGF-β, transforming growth factor-β; TLR, toll-like receptor; TNF-α, tumor necrosis factor-α; and VDR, vitamin D receptor. (Illustration credit: Ben Smith.)

    Figure 5.

    Figure 5. Autocrine modulation by 1,25(OH)2D of inflammation in macrophages. Toll-like receptor (TLR) ligands include exogenous infectious molecular patterns and endogenous products of cell death and matrix degradation.71 Activated vitamin D receptor (VDR) signaling downregulates bic gene transcription by blocking nuclear factor κB (NFκB) activation, resulting in negative feedback regulation of inflammation.51 IRF indicates interferon regulatory factor; MAPK, mitogen-activated protein kinase; RXR, retinoid X receptor; and SOCS, suppressors of cytokine signaling.

    An important feature of the modulation of immune function by 1,25(OH)2D is suppression of the development and responses of TH1 and TH17 cells and favoring Treg and TH2 cells.59 This is highly relevant to atherosclerosis given that cytotoxic T cells promote vulnerable plaque in apoE-deficient mice.72 There is animal model evidence that 1,25(OH)2D inhibits atherosclerosis by inducing tolerogenic dendritic cells and regulatory T cells58 and, in a clinical study, higher serum 25(OH)D concentrations were associated with a smaller plasma compartment of CD8+ cells in patients with type 1 diabetes mellitus.73

    Experimental evidence demonstrating modulation of immune and inflammatory cell differentiation and related cytokine release suggests important roles for vitamin D metabolites in the pathogenesis of atherosclerosis, aneurysm formation, and other inflammatory vascular disease. There is some limited clinical and epidemiological evidence to support this. A good example of stepping beyond the physiological boundaries for inflammatory and immune responses at low serum concentrations of 25(OH)D comes from patients with diabetes mellitus, where there is some intriguing information to suggest that polymorphisms in vitamin D metabolism genes may have a role in the early phases of islet autoimmunity.74 One randomized trial has shown that 1 year of vitamin D supplementation reduced circulating IL-6 concentrations in overweight subjects, although high sensitivity C-reactive protein concentrations increased.75 A much larger population study (NHANES) showed a strong inverse relationship between serum vitamin D and CRP concentrations in those with the lowest concentrations of 25(OH)D, suggesting that vitamin D supplementation for those with vitamin D deficiency might beneficially reduce inflammation.76 Finally, there is some evidence that vitamin D is an important influence on T cell regulation in patients with Behcet’s disease.77

    EC and VSMC Function

    EC dysfunction is associated with a proinflammatory and prothrombotic state, increased arterial stiffness and ultimately atherosclerosis. Human EC express VDRs and inflammatory cytokines cause rapid induction of endothelial CYP27B1 thereby allowing local production of 1,25(OH)2D.22,35 Exogenous vitamin D resulted in decreased proliferation of EC and increased monocyte adhesion, which was independent of intercellular adhesion molecule-1 or vascular cell adhesion molecule-1 induction. In addition, EC stress results in upregulated expression of the VDR. These effects on EC suggest an autocrine or paracrine role for 1,25(OH)2D with the potential to influence early atherogenesis by modulation of EC adhesion adversely and hence VSMC migration and proliferation.78 At least one of the mechanisms by which 1,25(OH)2D inhibits EC stimulation of VSMC proliferation in vitro involves the suppression of endothelin-induced activation of cyclin-dependent kinase 2.34

    Recent clinical studies also suggest a relationship between vitamin D status and endothelial function.79–82 Levels of 25(OH)D in healthy volunteers are independently associated with various measures of endothelial function, arterial stiffness, and coronary flow reserve.80,83 In a subgroup of participants with vitamin D deficiency, normalization of 25(OH)D levels at 6 months was associated with a significant increase in reactive hyperemia indices (monitoring endothelium-dependent relaxation). Similarly in other studies, treatment with vitamin D improved arterial stiffness (pulse wave velocity).84,85 Vitamin D deficiency is associated with increased EC expression of nuclear factor κB (NFκB) and IL-6, and inhibition of NFκB (with oral salsalate) improved endothelium-dependent dilatation to a greater extent in subjects with the lowest 25(OH)D levels.30 Low 25(OH)D levels are associated with reduced flow–mediated dilation of the brachial artery in patients with type II diabetes mellitus.86 It has been suggested, on the basis of in vitro evidence, that vitamin D may attenuate the adverse effects (including increased NFκB expression) of advanced glycation endproducts on EC.87

    In addition to any vascular effects mediated via EC, 1,25(OH)2D influences VSMC directly via the VDR (Table).88 The production of vascular endothelial growth factor by VSMC is stimulated by 1,25(OH)2D, and this may be relevant to endothelial repair.48 Vitamin D analogs have been shown to upregulate type-B endothelin receptor gene (which influences NO release) and downregulate the oxytocin receptor gene in human VSMC,41 a gene expression pattern that favors vessel relaxation. Exposure to 1,25(OH)2D increases proliferation of quiescent VSMC but decreases proliferation in nonquiescent cells.36,39 Migration of VSMC is also induced by 1,25(OH)2D via a nongenomic response.37 In addition, VSMC express CYP27B1 that can be upregulated by parathyroid hormone, providing a potential autocrine mechanism influencing VSMC proliferation and differentiation.21 These effects of 1,25(OH)2D are consistent with a role in physiological vascular remodeling although the relevance to either pathological intimal hyperplasia or carotid intima/media thickening is yet to be established.40

    The Renin–Angiotensin System

    Murine gene deletion or knockout (KO) studies provide in vivo evidence that 1,25(OH)2D is involved in the regulation of the renin–angiotensin system (RAS). This is relevant to CVD at multiple levels. Experimental atherosclerosis is accelerated in low-density lipoprotein receptor−/−/VDR−/− mice via loss of macrophage VDR signaling and resultant upregulation of local RAS.55 Renin gene expression is suppressed by 1,25(OH)2D via reduction in the activity of the cAMP response element in the renin gene promoter.89,90 In the VDR KO model, there is a marked increase in the expression of renin and consequently of angiotensin II production, resulting in hypertension and cardiac hypertrophy.89 Pancreatic RAS also seems to be upregulated in this model, and this is reversed by treatment with 1,25(OH)2D resulting in increased insulin secretion.91 In the CYP27B1 KO model, mice have elevated levels of renin, hypertension, and cardiac hypertrophy, which are reversed by treatment with 1,25(OH)2D.92 Activation of the VDR by 1,25(OH)2D also improves EC function by reduced reactive oxygen species production via downregulation of angiotensin II type 1 receptor expression.33

    Both renin activity and hypertension have been found to be inversely associated with 25(OH)D levels in clinical observational studies.93 For example in a cross-sectional analysis of patients with low renin hypertension, renin was inversely associated with 25(OH)D levels and positively associated with salt sensitivity, supporting a role for vitamin D metabolites in hypertension.94 In NHANES, the odds ratio for risk of hypertension in participants with 25(OH)D levels in the first versus fourth quartile was a modest 1.3 (95% confidence interval [CI], 1.13–1.49).95 A subsequent meta-analysis of 4 prospective and 14 cross-sectional studies confirmed that 25(OH)D level was inversely associated with hypertension with an odds ratio of 0.73 (95% CI, 0.63–0.84) with a significant dose–response effect.96

    The influence of vitamin D metabolites on both endothelial function and RAS suggests an important role in physiological control of vascular tone and blood pressure and hence in the pathophysiology of hypertension.

    Thrombosis

    Experimental data suggest that 1,25(OH)2D influences thrombotic tendency. Ohsawa et al54 demonstrated that 1,25(OH)2D downregulated tissue factor and upregulated thrombomodulin expression in cultured monocytic cells via a VDR-mediated mechanism. In an in vitro study of human VSMC, vitamin D analogs (paricalcitol and calcitriol) caused downregulation of plasminogen activator inhibitor-1 and thrombospondin-1 mRNA expression and protein production and upregulation of thrombomodulin.46 Given that plasminogen activator inhibitor-1 and thrombospondin-1 both involved thrombus formation, and thrombomodulin overexpression may reduce thrombosis,97 this pattern of effects of 1,25(OH)2D is consistent with an antithrombotic role. Results from a KO model confirmed initial in vitro studies, with VDR null mice exhibiting a prothrombotic state because of downregulation of both antithrombin and thrombomodulin and upregulation of tissue factor gene expression.98 Another antithrombotic effect of 1,25(OH)2D is the attenuation platelet activation by EC.99

    There are few clinical reports implicating vitamin D deficiency with increased thrombosis. In the 1958 British Birth Cohort, there was a significant inverse association between vitamin D status and tissue plasminogen activator antigen concentration and to a lesser extent with fibrinogen and D-dimer concentrations.100 Low levels of 25(OH)D in patients with antiphospholipid syndrome (a prothrombotic condition) have been associated with reduced expression of tissue factor.101 A recent population-based study (n=18 791) has found that there is a stepwise increase in risk of deep vein thrombosis for each lower tertile of 25(OH)D level.102 This association was independent of cardiovascular risk factors, albeit only in nonsmokers. Although there may be an association between venous thrombosis and atherosclerosis, the relevance of this observation to CVD is unknown.

    Matrix Homeostasis

    Several lines of evidence suggest that vitamin D metabolites play a role in matrix homeostasis. This may be significant in aneurysmal disease, which is characterized by inflammation, matrix destruction, and proteolysis.103,104 In vitro studies indicate that 1,25(OH)2D suppresses matrix-metalloproteinase (MMP) production in various cell types and, in the VDR KO mice, the expression of tissue inhibitor of matrix metalloproteinase-1 and tissue inhibitor of matrix metalloproteinase-3 is downregulated, and that of MMP-2 and MMP-9 is upregulated in cardiac muscle.60 There is some clinical evidence that vitamin D insufficiency is associated with increased circulating levels of MMP-2 and MMP-9.105,106

    In a study using cultured skin fibroblasts, VDR gene expression was decreased in individuals with Marfan syndrome.107 Given that the VDR is a negative regulator of transforming growth factor-β transcriptional activation,47 this could contribute to aneurysmal phenotype.107 However, vitamin D metabolites are also known to repress elastin gene expression via a post-transcriptional mechanism.45,108 Because most aortic elastin is synthesized during the fetal and early postnatal period,109 it has been hypothesized that exposure of excess vitamin D during fetal life could influence elastin deposition in the developing aorta, thereby predisposing an individual to aneurysm formation in later life.110 This is paradoxical given that low vitamin D status in adults may be associated with abdominal aortic aneurysm. Because exposure to excess vitamin D is now relatively rare, the significance of this hypothesis in humans is uncertain.

    As with occlusive arterial disease, there is some epidemiological evidence that vitamin D deficiency is associated with an increased risk of aneurysmal disease.111 In a large population-based study of older men (n=4233), there was a significant association between low level of 25OHD and abdominal aortic aneurysms ≥35 mm in diameter, and the level of 25OHD correlated with aneurysmal diameter in a dose–response fashion.112 A similar finding was noted in a small series of patients (n=236) with abdominal and thoracic aneurysms.111

    Cardiomyocyte Function and Cardiac Hypertrophy

    Cardiomyocytes express VDR, and their physiological function is influenced by 1,25(OH)2D.23,62 There is experimental evidence that vitamin D deficiency results in maladaptive cardiac remodeling attributable to progressive myocyte hypertrophy and interstitial fibrosis. The VDR KO mice exhibit ventricular hypertrophy and increased matrix turnover (see above).60,61 Because this model is associated with hypertension and elevated parathyroid hormone levels, both of which may cause cardiac hypertrophy,89,113 the mechanism for this effect of 1,25(OH)2D was unclear. In a model using selective deletion of the VDR gene from cardiomyocytes, Chen et al66 have recently confirmed a direct in vivo antihypertrophic effect of 1,25(OH)2D on cardiomyocytes, but with little effect on fibrosis. It seems that 1,25(OH)2D suppresses expression of modulatory calcineurin inhibitory protein 1, a direct downstream target of suppression of the calcineurin/NF of activated T cells. However, in a murine model of viral myocarditis, a vitamin D analog reduced myocardial fibrosis by inhibition of osteopontin expression.114 The secretion of atrial natriuretic peptide (which influences proliferation) is also suppressed by 1,25(OH)2D, although it is unclear whether this plays a role in any antihypertrophic effect.62 In addition, the expression of type 1 natiuretic peptide receptor-A, an inhibitor of RAS and myocardial hypertrophy, is increased by 1,25(OH)2D.63

    The rate and magnitude of cardiomyocyte sarcomere contraction is modulated by 1,25(OH)2D via interaction with caveolin-3 in t-tubules.67 This rapid nongenomic process is thought to be mediated by membrane-bound VDR. Cardiomyocyte relaxation is accelerated by 1,25(OH)2D, which may improve coronary perfusion during diastole.62 Intracellular calcium influx into cardiomyocytes is also increased by 1,25(OH)2D via modulation of β-adrenergic pathways.115

    The clinical significance of these experimental observations in cardiac tissue remains to be established. There is evidence that vitamin D deficiency during pregnancy is associated with dilated cardiomyopathy in infants.116 Although epidemiological studies have often demonstrated an association between vitamin D deficiency and heart failure in adults, the association may not be significant once adjustment for other risk factors is made.19,117 Furthermore 2 clinical trials of the effects of vitamin D in heart failure did not report any significant clinical benefits.118,119 An alternative suggestion is that low 25(OH)D concentrations are associated with poor prognosis in patients with heart failure, an effect mediated by activation of RAS and inflammation.120

    Vascular Calcification

    Vascular calcification is seen in the intima in atherosclerosis, the media in both aneurysmal disease and diabetic arterial disease, and in valvular heart disease. This ectopic mineralization process is poorly understood and has been recently reviewed elsewhere.121 The present review will be limited to aspects of vascular calcification that are relevant to vitamin D and its metabolites. The relationship between vitamin D and vascular calcification is complex and may be partly dose dependent: excess vitamin D in the presence of renal impairment results in experimental vascular calcification, yet in contrast, 1,25(OH)2D levels are inversely associated with coronary artery calcification.122 The actions of 1,25(OH)2D on mineral metabolism (increasing phosphate and calcium concentrations) and on osteoblastic gene expression may favor vascular calcification, whereas other effects such as modulation of inflammation may reduce vascular calcification.13

    High dose vitamin D metabolites and analogs induce an osteoblastic phenotype in VSMC,42,123 and this has been used in animal models to produce vascular calcification in both the presence124,125 and absence126 of uremia. Macrophages also influence vascular calcification by enhancing osteogenic phenotype in VSMC.127 Treatment of cocultured macrophages and VSMC with VDR activators induces osteopontin and inhibits bone morphogenetic protein 2 and tumor necrosis factor-α expression, with reversal of the effect of macrophages on VSMC calcification.128 There is some evidence that 1,25(OH)2D increases in vitro VSMC calcification42,43 although this has not be confirmed in other studies.128 Wu-Wong et al41 reported that vitamin D analogs did not influence expression of alkaline phosphatase, osteopontin, or receptor activator for NFκB ligand in VSMC. However, in an another study, exposure of VSMC to clinically relevant concentrations of 1,25(OH)2D and phosphate increased the expression of osteoblast-associated genes such as matrix gla protein, osteopontin, and osteonectin.42 In the VDR−/− and Low-Density Lipoprotein receptor−/− mouse model, a low vitamin D diet increased aortic calcification via a mechanism involving upregulation of osteoblast transcription factors.44 These differences in the influence of 1,25(OH)2D or its analogs on both calcification and the gene expression of calcification factors may be pharmacological rather than physiological. Because vitamin D is activated to 1,25(OH)2D in the kidney, uremia changes homeostatic mechanisms, where vitamin D signaling plays a critical role, with vitamin D agonists offering therapeutic benefits.129 In a mouse chronic kidney disease model, therapeutic dosage (sufficient to correct secondary hyperparathyroidism) of the VDR activator, paricalcitol, reduced aortic osteoblastic gene expression and calcification, but high dosage (400 ng/kg) caused a significant increase in calcification.130 This highlights the dose-dependent role of vitamin D in vascular calcification, and presumably cardiovascular health.

    Klotho is a gene first described as being associated with premature aging in mice. It is a 130-kDa transmembrane protein that is mainly expressed in the distal nephron.131 The extracellular domain of Klotho is subject to proteolytic cleavage, and the soluble form of Klotho is secreted into the circulation. Klotho has been suggested as a master regulator of arterial calcification. It is a coreceptor for fibroblast growth factor 23 and together they maintain calcium and phosphate balance. Their expression is increased by activation of VDR, with promotion of phosphaturia and autoregulatory inhibition of the conversion of 25(OH)D to 1,25(OH)2D. Two recent studies, one in mice and one in humans, have indicated strongly that Klotho is protective against vascular calcification by preventing the conversion of VSMC to an osteotypic phenotype.132,133 Ectopic calcification seen in mice models with loss of function for either Klotho or fibroblast growth factor 23 is prevented by genetically reducing 1,25(OH)2D production (possibly by reversing hyperphospatemia).13,134 Klotho also influences endothelium-dependent vasodilation and inflammatory pathways involving VSMC.131 Thus, interactions between Klotho, fibroblast growth factor 23, and vitamin D metabolites are likely of critical importance to the development of vascular calcification.

    Clinical and Epidemiological Studies of Vitamin D Deficiency and CVD

    Significant associations between low vitamin D status and both prevalent135 and incident136 degenerative CVD have been reported in large-scale studies using composite end points. Vitamin D deficiency has also been linked to several cardiovascular risk factors such as hypertension (see above), dyslipidemia, and diabetes mellitus.

    Some clinical studies have shown that high levels of 25(OH)D are associated with favorable lipid profile.137,138 However, these observations are subject to confounding, and a recent meta-analysis of 12 clinical trials (1346 participants) of the influence of vitamin D supplementation on lipid profiles showed little evidence of a beneficial effect.139 In a large population-based study (n=107 811) using serial laboratory results, Ponda et al138 have also cast doubt on the impact of vitamin D on lipid levels. In a subgroup of 6260 subjects with vitamin D deficiency at baseline, and biochemical evidence of improved vitamin D status 4 to 26 weeks later (resulting from vitamin D2 supplementation), there was no improvement in lipid profile.

    Several cross-sectional studies have demonstrated a consistent relationship between vitamin D deficiency and diabetes mellitus. In NHANES III, a 25(OH)D level in the first versus fourth quartile was associated with diabetes mellitus with an odds ratio of 1.73 (95% CI, 1.38–2.16).95 There is a negative correlation between insulin resistance and β cell function in individuals at risk of type 2 diabetes mellitus.140 Longitudinal studies have also shown that higher baseline vitamin D status reduces the risk of incident diabetes mellitus.5,141 Despite the experimental and human observational evidence implicating vitamin D in diabetes mellitus, interventional studies have been inconsistent or inconclusive.142,143

    Coronary Heart Disease and CVD Mortality

    Several large-scale prospective studies using a range of methodologies have found that baseline 25(OH)D concentration is associated with the incidence of coronary heart disease events in a dose–response fashion. In the Health Professionals Follow-up Study (n=18 225 men aged 40–75 years who were free of CVD at baseline), there was a graded independent relationship between low levels of 25(OH)D and risk of myocardial infarction; for example, the relative risk for levels ≤37.5 nmol/L versus ≥75 nmol/L was 2.09 (95% CI, 1.24–3.53).144 In a meta-analysis of 18 prospective studies (n=82 982 participants of mixed ethnicity), the risk of any coronary heart disease events was increased by 33% (95% CI, 28%–38%) for the lowest versus the highest quartile of 25(OH)D level.145 Cerebrovascular disease, although less studied than coronary heart disease, shows a similar pattern: in a meta-analysis of 10 prospective cohort studies (n=58 384 participants with 2644 events), for individuals with 25OHD levels in the lowest versus highest quartile, the hazard ratio for ischemic stroke was 1.54 (95% CI, 1.43–1.65).146

    Observational studies have also shown a graded relationship between vitamin D deficiency and risk of CVD (Figure 6).147–153 Significant associations between vitamin D deficiency and CVD mortality have been reported in older adults,148,152,153 although in a report from NHANES of 13 331 participants, this was not significant.147 A recent population-based study of 9146 younger (30–71 years) adults found significant associations with all-cause mortality but not CVD mortality.149 In a meta-analysis of 17 prospective studies (n=77 155 participants of mixed ethnicity), the risk of any early death (as a surrogate for cardiovascular death) was increased by 35% (95% CI, 31%–42%) for the lowest versus the highest quartile of 25(OH)D level.145

    Figure 6.

    Figure 6. Dose–response association between circulating 25(OH)D and risk of cardiovascular disease in 16 independent studies. Circles indicate the relative risk in each study. The size of the circle is proportional to the precision of the relative risk (RR; inverse of its variance). The gray-shaded region shows the 95% confidence intervals (CIs) around the regression line. Adapted from Wang et al153 with permission of the publisher. Copyright © 2012, American Heart Association.Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.

    Peripheral Arterial Disease and Extent of Atherosclerosis

    Several cross-sectional population studies have demonstrated an association between the extent of peripheral arterial disease (PAD) in subjects and vitamin D deficiency.154,155 In such studies, PAD is usually defined by measuring the ankle brachial systolic pressure index, which is a specific marker of lower limb atherosclerosis (and an index of overall atherosclerotic burden) rather than a clinical manifestation of lower limb disease. In NHANES 2001 to 2004, the risk of having PAD (based on an ankle brachial index <0.9; n=4818) was almost twice as high for subjects with a 25(OH)D level <50 nmol/L versus those with ≥75 nmol/L, odds ratio 1.82 (95% CI, 1.26–2.61).154

    In addition to any relationship between vitamin D deficiency and PAD as a marker of atherosclerosis, the role of immobility in both may be important. PAD is associated with decreased mobility (which indirectly reduces sun exposure and impairs vitamin D synthesis), sarcopenia, and an increased risk of hip fracture.156,157 In this situation, vitamin D deficiency could be considered a consequence, rather than a cause, of both PAD and osteoporosis.155

    Therapeutic Implications

    Although vitamin D deficiency is undoubtedly bad for cardiovascular health, there is also some evidence that high levels of vitamin D may also be associated with adverse arterial remodeling and poor outcomes. In NHANES III, there was a U-shaped relationship between vitamin D and mortality risk, with an apparent increase in mortality, particularly in women, with 25(OH)D levels >50 ng/L.140 Although 1 meta-analysis that included 8 studies that assessed relatively high (>65 nmol/L) levels of 25(OH) found no significant change in risk of CVD,153 another meta-analysis reported evidence of increased mortality with 25(OH)D concentrations >97.5 nmol/L.150 Although part of this increased mortality at high levels of 25(OH)D seems to be attributable to cancer, a similar pattern has been reported for cardiovascular outcomes in some studies. In the Framingham Offspring Study, there was a nonlinear relationship between baseline vitamin D status and the adjusted hazard ratio for incident cardiovascular events.136 Carotid intima/media thickness and cardiac calcification scores were also found to have a bimodal distribution across 25(OH)D levels in a study comparing children on dialysis with controls.158 These studies did not contain enough individuals with high levels of 25(OH)D to establish whether there is a threshold above which the risk of adverse cardiovascular events is significant (Figure 6). As such, the importance of the various nonlinear patterns remains to be established, and further research is required. Nevertheless a recent review of the risks of vitamin D supplementation suggests that “…there should be a degree of caution about recommending high serum 25(OH)D concentrations for the entire population.”159

    Ethnicity is relevant when interpreting circulating levels of 25(OH)D because levels are lower in blacks than in whites. There is evidence that low levels of 25(OH)D are associated with increased risk of coronary heart disease events in whites and Chinese but not among black or Hispanic people.160 The reason for this difference is unclear but may relate to differential CYP27B1 or 24-hydroxylase activity and hence tissue availability of 1,25(OH)2D.161 These differences need to be taken into account when considering therapeutic intervention, at least in the context of cardiovascular risk.

    The major problem with epidemiological studies is that vitamin D status may just be a surrogate marker for sociodemographic risk factors and poor metabolic health, thereby confounding any observational associations with CVD.162,163 The importance of this confounding has been highlighted in gene association studies. Although a large study suggested that a variant within the VDR gene (rs7968585) increased the composite risk of outcomes, which included myocardial infarction,164 a recent Mendelian randomization study failed to demonstrate any consistent relationship between various genetic variants associated 25(OH)D metabolism and cardiovascular outcomes.16 This raises important questions concerning the role of vitamin D deficiency in the causal pathway of CVD, although the role of variants in VDR and other components of vitamin D signaling has not been extensively investigated.

    Despite the wide-ranging experimental and epidemiological evidence implicating 1,25(OH)2D in many aspects of cardiovascular health, a meta-analysis of 51 trials of vitamin D in the prevention of various cardiovascular outcomes showed no overall benefit.165 At present, it is unclear whether vitamin D supplementation can reduce the risk or consequences of CVD, and it is not recommended for this indication.9,162

    Future Directions

    Although the results of current trials assessing the role of vitamin D supplementation in the prevention of CVD are awaited with interest,166 there are important knowledge gaps which need addressing. First, there is a requirement to better define the therapeutic window for vitamin D supplementation with respect to age and ethnicity, probably in tandem with better quality control of vitamin D metabolite assays. Second, more needs to be learned about the autocrine and paracrine influence of 1,25(OH)2D on cardiovascular physiology and pathology at a cellular level, particularly with respect to control of inflammatory networks and local calcification. Areas of potential interest include tissue-specific patterns of 1,25(OH)2D–induced gene expression, the role of nongenomic actions of 1,25(OH)2D, and the relevance of 1,25(OH)2D to matrix homeostasis in aneurysmal disease, diabetic arterial disease, and calcific aortic valve disease. Also of importance is the bioactivity of 1,25(OH)2D within vascular tissue and its autoregulation, which is dependent on 25(OH)D acting, not only as a substrate for 1,25(OH)2D production, but also as an inducer of CYP27B1 and VDR expression.30 Although 1,25(OH)2D limits its own availability by induction of 24-hydroxylase in undifferentiated monocytes, this control is antagonized in activated macrophages by interferon-γ–induced Stat-1α (signal transducers and activators of transcription-1 α) production.167 Given the prominence of interferon-γ in atherosclerosis, the significance of this potentially unregulated local production of 1,25(OH)2D is intriguing.

    Insights into the importance of 1,25(OH)2D in regulating the cell cycle in cancer and other pathologies have the potential to inform cardiovascular research. The rates of proliferation, migration, and apoptosis in VSMC are normally low but are all increased in atherosclerosis and injury-induced intimal hyperplasia. Most of these cellular processes are influenced by 1,25(OH)2D in cancer, including the regulation of cyclins and their dependent kinases; the transcription of p53 and other genes affecting apoptosis; the expression of insulin-like growth receptors and binding proteins influencing mitogenic pathways; reactive oxygen species generation; and associated effects on inflammation and proliferation.168 Interactions between 1,25(OH)2D and cell adhesion molecules may also be relevant: the Wnt/β–catenin pathway, which is important in VSMC function and atherosclerosis,169 is regulated by 1,25(OH)2D in cancer cells; the expression of E-cadherin is increased by 1,25(OH)2D, thereby normalizing cellular shape, adhesion, and homophilic interactions.168 The influence of 1,25(OH)2D on all these pathways in models of atherosclerotic or other CVD merits further exploration.

    Nonstandard Abbreviations and Acronyms

    1,25(OH)2D

    1α,25-dihydroxyvitamin D

    25(OH)D

    25-hydroxyvitamin D

    CVD

    cardiovascular disease

    CYP27B1

    1α-hydroxylase

    EC

    endothelial cell

    IL

    interleukin

    KO

    knockout

    MMP

    matrix-metalloproteinase

    NFκB

    nuclear factor κB

    PAD

    peripheral arterial disease

    RAS

    renin–angiotensin system

    VDR

    vitamin D receptor

    VSMC

    vascular smooth muscle cell

    Acknowledgments

    We are grateful to staff in the Audio-visual Department of Fremantle Hospital for preparation of artwork.

    Sources of Funding

    This work was supported by institutional funding only.

    Disclosures

    None.

    Footnotes

    In November 2013, the average time from submission to first decision for all original research papers submitted to Circulation Research was 14.6 days.

    Correspondence to Paul Norman, MD, School of Surgery, University of Western Australia, Fremantle Hospital, PO Box 480, Fremantle, Western Australia 6959, Australia. E-mail

    References

    • 1. Holick MF. Vitamin D deficiency.N Engl J Med. 2007; 357:266–281.CrossrefMedlineGoogle Scholar
    • 2. Rosen CJ, Adams JS, Bikle DD, Black DM, Demay MD, Manson JE, Murad M, Kovacs CS. The nonskeletal effects of vitamin D: an Endocrine Society Scientific statement.Endocr Rev. 2011; 33:456–492.CrossrefGoogle Scholar
    • 3. Weishaar RE, Simpson RU. Vitamin D3 and cardiovascular function in rats.J Clin Invest. 1987; 79:1706–1712.CrossrefMedlineGoogle Scholar
    • 4. Scragg R. Seasonality of cardiovascular disease mortality and the possible protective effect of ultra-violet radiation.Int J Epidemiol. 1981; 10:337–341.CrossrefMedlineGoogle Scholar
    • 5. Motiwala SR, Wang TJ. Vitamin D and cardiovascular risk.Curr Hypertens Rep. 2012; 14:209–218.CrossrefMedlineGoogle Scholar
    • 6. Richart T, Li Y, Staessen JA. Renal versus extrarenal activation of vitamin D in relation to atherosclerosis, arterial stiffening, and hypertension.Am J Hypertens. 2007; 20:1007–1015.CrossrefMedlineGoogle Scholar
    • 7. Brouwer-Brolsma EM, Bischoff-Ferrari HA, Bouillon R, et al.. Vitamin D: do we get enough? A discussion between vitamin D experts in order to make a step towards the harmonisation of dietary reference intakes for vitamin D across Europe.Osteoporos Int. 2013; 24:1567–1577.CrossrefMedlineGoogle Scholar
    • 8. Battault S, Whiting SJ, Peltier SL, Sadrin S, Gerber G, Maixent JM. Vitamin D metabolism, functions and needs: from science to health claims.Eur J Nutr. 2013; 52:429–441.CrossrefMedlineGoogle Scholar
    • 9. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM; Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2011; 96:1911–1930.CrossrefMedlineGoogle Scholar
    • 10. Dawson-Hughes B. Racial/ethnic considerations in making recommendations for vitamin D for adult and elderly men and women.Am J Clin Nutr. 2004; 80:1763S–1766S.CrossrefMedlineGoogle Scholar
    • 11. Institute of Medicine of the National Academies. http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx. Accessed March 7, 2013.Google Scholar
    • 12. Lai JK, Lucas RM, Banks E, Ponsonby AL; Ausimmune Investigator Group. Variability in vitamin D assays impairs clinical assessment of vitamin D status.Intern Med J. 2012; 42:43–50.CrossrefMedlineGoogle Scholar
    • 13. Razzaque MS. The dualistic role of vitamin D in vascular calcifications.Kidney Int. 2011; 79:708–714.CrossrefMedlineGoogle Scholar
    • 14. Nagy L, Szanto A, Szatmari I, Széles L. Nuclear hormone receptors enable macrophages and dendritic cells to sense their lipid environment and shape their immune response.Physiol Rev. 2012; 92:739–789.CrossrefMedlineGoogle Scholar
    • 15. Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen JP. Genetics and biology of vitamin D receptor polymorphisms.Gene. 2004; 338:143–156.CrossrefMedlineGoogle Scholar
    • 16. Jorde R, Schirmer H, Wilsgaard T, Joakimsen RM, Mathiesen EB, Njølstad I, Løchen ML, Figenschau Y, Berg JP, Svartberg J, Grimnes G. Polymorphisms related to the serum 25-hydroxyvitamin D level and risk of myocardial infarction, diabetes, cancer and mortality. The Tromsø Study.PLoS One. 2012; 7:e37295.CrossrefMedlineGoogle Scholar
    • 17. Dastani Z, Li R, Richards B. Genetic regulation of vitamin D levels.Calcif Tissue Int. 2013; 92:106–117.CrossrefMedlineGoogle Scholar
    • 18. Mithal A, Wahl DA, Bonjour JP, Burckhardt P, Dawson-Hughes B, Eisman JA, El-Hajj Fuleihan G, Josse RG, Lips P, Morales-Torres J; IOF Committee of Scientific Advisors (CSA) Nutrition Working Group. Global vitamin D status and determinants of hypovitaminosis D.Osteoporos Int. 2009; 20:1807–1820.CrossrefMedlineGoogle Scholar
    • 19. Kim DH, Sabour S, Sagar UN, Adams S, Whellan DJ. Prevalence of hypovitaminosis D in cardiovascular diseases (from the National Health and Nutrition Examination Survey 2001 to 2004).Am J Cardiol. 2008; 102:1540–1544.CrossrefMedlineGoogle Scholar
    • 20. Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A, Luderer HF, Lieben L, Mathieu C, Demay M. Vitamin D and human health: lessons from vitamin D receptor null mice.Endocr Rev. 2008; 29:726–776.CrossrefMedlineGoogle Scholar
    • 21. Somjen D, Weisman Y, Kohen F, Gayer B, Limor R, Sharon O, Jaccard N, Knoll E, Stern N. 25-hydroxyvitamin D3-1alpha-hydroxylase is expressed in human vascular smooth muscle cells and is upregulated by parathyroid hormone and estrogenic compounds.Circulation. 2005; 111:1666–1671.LinkGoogle Scholar
    • 22. Merke J, Milde P, Lewicka S, Hügel U, Klaus G, Mangelsdorf DJ, Haussler MR, Rauterberg EW, Ritz E. Identification and regulation of 1,25-dihydroxyvitamin D3 receptor activity and biosynthesis of 1,25-dihydroxyvitamin D3. Studies in cultured bovine aortic endothelial cells and human dermal capillaries.J Clin Invest. 1989; 83:1903–1915.CrossrefMedlineGoogle Scholar
    • 23. Tishkoff DX, Nibbelink KA, Holmberg KH, Dandu L, Simpson RU. Functional vitamin D receptor (VDR) in the t-tubules of cardiac myocytes: VDR knockout cardiomyocyte contractility.Endocrinology. 2008; 149:558–564.CrossrefMedlineGoogle Scholar
    • 24. Guillot X, Semerano L, Saidenberg-Kermanac’h N, Falgarone G, Boissier MC. Vitamin D and inflammation.Joint Bone Spine. 2010; 77:552–557.CrossrefMedlineGoogle Scholar
    • 25. Silvagno F, De Vivo E, Attanasio A, Gallo V, Mazzucco G, Pescarmona G. Mitochondrial localization of vitamin D receptor in human platelets and differentiated megakaryocytes.PLoS One. 2010; 5:e8670.CrossrefMedlineGoogle Scholar
    • 26. Norman AW. Vitamin D receptor: new assignments for an already busy receptor.Endocrinology. 2006; 147:5542–5548.CrossrefMedlineGoogle Scholar
    • 27. Yanagisawa J, Yanagi Y, Masuhiro Y, Suzawa M, Watanabe M, Kashiwagi K, Toriyabe T, Kawabata M, Miyazono K, Kato S. Convergence of transforming growth factor-beta and vitamin D signaling pathways on SMAD transcriptional coactivators.Science. 1999; 283:1317–1321.CrossrefMedlineGoogle Scholar
    • 28. Karlic H, Varga F. Impact of vitamin D metabolism on clinical epigenics.Clin Epigenet. 2011; 2:55–61.CrossrefMedlineGoogle Scholar
    • 29. Huhtakangas JA, Olivera CJ, Bishop JE, Zanello LP, Norman AW. The vitamin D receptor is present in caveolae-enriched plasma membranes and binds 1 alpha,25(OH)2-vitamin D3 in vivo and in vitro.Mol Endocrinol. 2004; 18:2660–2671.CrossrefMedlineGoogle Scholar
    • 30. Zhang Y, Leung DY, Richers BN, Liu Y, Remigio LK, Riches DW, Goleva E. Vitamin D inhibitsmonocyte/macrophage proinflammatory cytokine production.J Immunol. 2012; 188:2127–35.CrossrefMedlineGoogle Scholar
    • 31. Jones G. Extrarenal vitamin D activation and interactions between vitamin D2, vitamin D3, and vitamin D analogs.Annu Rev Nutr. 2013; 33:23–44.CrossrefMedlineGoogle Scholar
    • 32. Jablonski KL, Chonchol M, Pierce GL, Walker AE, Seals DR. 25-Hydroxyvitamin D deficiency is associated with inflammation-linked vascular endothelial dysfunction in middle-aged and older adults.Hypertension. 2011; 57:63–69.LinkGoogle Scholar
    • 33. Mill C, George SJ. Wnt signalling in smooth muscle cells and its role in cardiovascular disorders.Cardiovasc Res. 2012; 95:233–240.CrossrefMedlineGoogle Scholar
    • 34. Wong MS, Delansorne R, Man RY, Vanhoutte PM. Vitamin D derivatives acutely reduce endothelium-dependent contractions in the aorta of the spontaneously hypertensive rat.Am J Physiol Heart Circ Physiol. 2008; 295:H289–H296.CrossrefMedlineGoogle Scholar
    • 35. Dong J, Wong SL, Lau CW, Lee HK, Ng CF, Zhang L, Yao X, Chen ZY, Vanhoutte PM, Huang Y. Calcitriol protects renovascular function in hypertension by down-regulating angiotensin II type 1 receptors and reducing oxidative stress.Eur Heart J. 2012; 33:2980–2990.CrossrefMedlineGoogle Scholar
    • 36. Chen S, Law CS, Gardner DG. Vitamin D-dependent suppression of endothelin-induced vascular smooth muscle cell proliferation through inhibition of CDK2 activity.J Steroid Biochem Mol Biol. 2010; 118:135–141.CrossrefMedlineGoogle Scholar
    • 37. Zehnder D, Bland R, Chana RS, Wheeler DC, Howie AJ, Williams MC, Stewart PM, Hewison M. Synthesis of 1,25-dihydroxyvitamin D(3) by human endothelial cells is regulated by inflammatory cytokines: a novel autocrine determinant of vascular cell adhesion.J Am Soc Nephrol. 2002; 13:621–629.MedlineGoogle Scholar
    • 38. Mitsuhashi T, Morris RC, Ives HE. 1,25-dihydroxyvitamin D3 modulates growth of vascular smooth muscle cells.J Clin Invest. 1991; 87:1889–1895.CrossrefMedlineGoogle Scholar
    • 39. Rebsamen MC, Sun J, Norman AW, Liao JK. 1alpha,25-dihydroxyvitamin D3 induces vascular smooth muscle cell migration via activation of phosphatidylinositol 3-kinase.Circ Res. 2002; 91:17–24.LinkGoogle Scholar
    • 40. Molinari C, Uberti F, Grossini E, Vacca G, Carda S, Invernizzi M, Cisari C. 1α,25-dihydroxycholecalciferol induces nitric oxide production in cultured endothelial cells.Cell Physiol Biochem. 2011; 27:661–668.CrossrefMedlineGoogle Scholar
    • 41. Bukoski RD, DeWan P, McCarron DA. 1,25 (OH)2 vitamin D3 modifies growth and contractile function of vascular smooth muscle of spontaneously hypertensive rats.Am J Hypertens. 1989; 2:553–556.CrossrefMedlineGoogle Scholar
    • 42. Lamawansa MD, Wysocki SJ, House AK, Norman PE. Vitamin D3 exacerbates intimal hyperplasia in balloon-injured arteries.Br J Surg. 1996; 83:1101–1103.CrossrefMedlineGoogle Scholar
    • 43. Wu-Wong JR, Nakane M, Ma J, Ruan X, Kroeger PE. Effects of Vitamin D analogs on gene expression profiling in human coronary artery smooth muscle cells.Atherosclerosis. 2006; 186:20–28.CrossrefMedlineGoogle Scholar
    • 44. Shalhoub V, Shatzen E, Henley C, Boedigheimer M, McNinch J, Manoukian R, Damore M, Fitzpatrick D, Haas K, Twomey B, Kiaei P, Ward S, Lacey DL, Martin D. Calcification inhibitors and Wnt signaling proteins are implicated in bovine artery smooth muscle cell calcification in the presence of phosphate and vitamin D sterols.Calcif Tissue Int. 2006; 79:431–442.CrossrefMedlineGoogle Scholar
    • 45. Jono S, Nishizawa Y, Shioi A, Morii H. 1,25-Dihydroxyvitamin D3 increases in vitro vascular calcification by modulating secretion of endogenous parathyroid hormone-related peptide.Circulation. 1998; 98:1302–1306.CrossrefMedlineGoogle Scholar
    • 46. Schmidt N, Brandsch C, Kühne H, Thiele A, Hirche F, Stangl GI. Vitamin D receptor deficiency and low vitamin D diet stimulate aortic calcification and osteogenic key factor expression in mice.PLoS One. 2012; 7:e35316.CrossrefMedlineGoogle Scholar
    • 47. Pierce RA, Kolodziej ME, Parks WC. 1,25-Dihydroxyvitamin D3 represses tropoelastin expression by a posttranscriptional mechanism.J Biol Chem. 1992; 267:11593–11599.MedlineGoogle Scholar
    • 48. Wu-Wong JR, Nakane M, Ma J. Vitamin D analogs modulate the expression of plasminogen activator inhibitor-1, thrombospondin-1 and thrombomodulin in human aortic smooth muscle cells.J Vasc Res. 2007; 44:11–18.CrossrefMedlineGoogle Scholar
    • 49. Wu Y, Craig TA, Lutz WH, Kumar R. Identification of 1 alpha,25-dihydroxyvitamin D3 response elements in the human transforming growth factor beta 2 gene.Biochemistry. 1999; 38:2654–2660.CrossrefMedlineGoogle Scholar
    • 50. Cardus A, Panizo S, Encinas M, Dolcet X, Gallego C, Aldea M, Fernandez E, Valdivielso JM. 1,25-dihydroxyvitamin D3 regulates VEGF production through a vitamin D response element in the VEGF promoter.Atherosclerosis. 2009; 204:85–89.CrossrefMedlineGoogle Scholar
    • 51. Chen Y, Liu W, Sun T, Huang Y, Wang Y, Deb DK, Yoon D, Kong J, Thadhani R, Li YC. 1,25-Dihydroxyvitamin D promotes negative feedback regulation of TLR signaling via targeting microRNA-155-SOCS1 in macrophages.J Immunol. 2013; 190:3687–3695.CrossrefMedlineGoogle Scholar
    • 52. Helming L, Böse J, Ehrchen J, Schiebe S, Frahm T, Geffers R, Probst-Kepper M, Balling R, Lengeling A. 1alpha,25-Dihydroxyvitamin D3 is a potent suppressor of interferon gamma-mediated macrophage activation.Blood. 2005; 106:4351–4358.CrossrefMedlineGoogle Scholar
    • 53. Dickie LJ, Church LD, Coulthard LR, Mathews RJ, Emery P, McDermott MF. Vitamin D3 down-regulates intracellular Toll-like receptor 9 expression and Toll-like receptor 9-induced IL-6 production in human monocytes.Rheumatology (Oxford). 2010; 49:1466–1471.CrossrefMedlineGoogle Scholar
    • 54. Almerighi C, Sinistro A, Cavazza A, Ciaprini C, Rocchi G, Bergamini A. 1Alpha,25-dihydroxyvitamin D3 inhibits CD40L-induced pro-inflammatory and immunomodulatory activity in human monocytes.Cytokine. 2009; 45:190–197.CrossrefMedlineGoogle Scholar
    • 55. Ohsawa M, Koyama T, Yamamoto K, Hirosawa S, Kamei S, Kamiyama R. 1alpha,25-dihydroxyvitamin D(3) and its potent synthetic analogs downregulate tissue factor and upregulate thrombomodulin expression in monocytic cells, counteracting the effects of tumor necrosis factor and oxidized LDL.Circulation. 2000; 102:2867–2872.CrossrefMedlineGoogle Scholar
    • 56. Riek AE, Oh J, Sprague JE, Timpson A, de las Fuentes L, Bernal-Mizrachi L, Schechtman KB, Bernal-Mizrachi C. Vitamin D suppression of endoplasmic reticulum stress promotes an antiatherogenic monocyte/macrophage phenotype in type 2 diabetic patients.J Biol Chem. 2012; 287:38482–38494.CrossrefMedlineGoogle Scholar
    • 57. Szeto FL, Reardon CA, Yoon D, Wang Y, Wong KE, Chen Y, Kong J, Liu SQ, Thadhani R, Getz GS, Li YC. Vitamin D receptor signaling inhibits atherosclerosis in mice.Mol Endocrinol. 2012; 26:1091–1101.CrossrefMedlineGoogle Scholar
    • 58. Oh J, Weng S, Felton SK, Bhandare S, Riek A, Butler B, Proctor BM, Petty M, Chen Z, Schechtman KB, Bernal-Mizrachi L, Bernal-Mizrachi C. 1,25(OH)2 vitamin d inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus.Circulation. 2009; 120:687–698.LinkGoogle Scholar
    • 59. Takeda M, Yamashita T, Sasaki N, Nakajima K, Kita T, Shinohara M, Ishida T, Hirata K. Oral administration of an active form of vitamin D3 (calcitriol) decreases atherosclerosis in mice by inducing regulatory T cells and immature dendritic cells with tolerogenic functions.Arterioscler Thromb Vasc Biol. 2010; 30:2495–2503.LinkGoogle Scholar
    • 60. Boonstra A, Barrat FJ, Crain C, Heath VL, Savelkoul HF, O’Garra A. 1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells.J Immunol. 2001; 167:4974–4980.CrossrefMedlineGoogle Scholar
    • 61. Rahman A HS, Ahmed S, Nibbelink K, Simpson RU. Heart extracellular matrix gene expression profile in the vitamin D knockout mice.J Steroid Biochem Mol Biol. 2007; 103:416–419.CrossrefMedlineGoogle Scholar
    • 62. Pilz S, Tomaschitz A, Drechsler C, Dekker JM, März W. Vitamin D deficiency and myocardial diseases.Mol Nutr Food Res. 2010; 54:1103–1113.MedlineGoogle Scholar
    • 63. Xiang W, Kong J, Chen S, Cao LP, Qiao G, Zheng W, Liu W, Li X, Gardner DG, Li YC. Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems.Am J Physiol Endocrinol Metab. 2005; 288:E125–E132.CrossrefMedlineGoogle Scholar
    • 64. Chen S, Ni X-P, Humphreys MH, Gardner DG. 1,25(OH)2-dihydroxyvitamin D amplifies type A natiuretic peptide expression and activity in target cells.J Am Soc Nephrol. 2005; 16:329–339.CrossrefMedlineGoogle Scholar
    • 65. Yamamoto T, Kozawa O, Tanabe K, Akamatsu S, Matsuno H, Dohi S, Hirose H, Uematsu T. 1,25-dihydroxyvitamin D3 stimulates vascular endothelial growth factor release in aortic smooth muscle cells: role of p38 mitogen-activated protein kinase.Arch Biochem Biophys. 2002; 398:1–6.CrossrefMedlineGoogle Scholar
    • 66. Chen S, Law CS, Grigsby CL, Olsen K, Hong TT, Zhang Y, Yeghiazarians Y, Gardner DG. Cardiomyocyte-specific deletion of the vitamin D receptor gene results in cardiac hypertrophy.Circulation. 2011; 124:1838–1847.LinkGoogle Scholar
    • 67. Li Q, Gardner DG. Negative regulation of the human atrial natriuretic peptide gene by 1,25-dihydroxyvitamin D3.J Biol Chem. 1994; 269:4934–4939.MedlineGoogle Scholar
    • 68. Zhao G, Simpson RU. Interaction between vitamin D receptor with caveolin-3 and regulation by 1,25-dihydroxyvitamin D3 in adult rat cardiomyocytes.J Steroid Biochem Mol Biol. 2010; 121:159–163.CrossrefMedlineGoogle Scholar
    • 69. O’Connell TD, Simpson RU. 1,25-Dihydroxyvitamin D3 regulation of myocardial growth and c-myc levels in the rat heart.Biochem Biophys Res Commun. 1995; 213:59–65.CrossrefMedlineGoogle Scholar
    • 70. Lahoute C, Herbin O, Mallat Z, Tedgui A. Adaptive immunity in atherosclerosis: mechanisms and future therapeutic targets.Nat Rev Cardiol. 2011; 8:348–358.CrossrefMedlineGoogle Scholar
    • 71. O’Connell TD, Weishaar RE, Simpson RU. Regulation of myosin isozyme expression by vitamin D3 deficiency and 1,25-dihydroxyvitamin D3 in the rat heart.Endocrinology. 1994; 134:899–905.CrossrefMedlineGoogle Scholar
    • 72. Kyaw T, Winship A, Tay C, Kanellakis P, Hosseini H, Cao A, Li P, Tipping P, Bobik A, Toh BH. Cytotoxic and proinflammatory CD8+ T lymphocytes promote development of vulnerable atherosclerotic plaques in apoE-deficient mice.Circulation. 2013; 127:1028–1039.LinkGoogle Scholar
    • 73. Rose K, Penna-Martinez M, Klahold E, Kärger D, Shoghi F, Kahles H, Bayer M, Hintermann E, Pfeilschifter JM, Badenhoop K, Ramos-Lopez E, Christen U. Influence of the vitamin D plasma level and vitamin D-related genetic polymorphisms on the immune status of patients with type 1 diabetes: a pilot study.Clin Exp Immunol. 2013; 171:171–185.CrossrefMedlineGoogle Scholar
    • 74. Frederiksen BN, Kroehl M, Fingerlin TE, Wong R, Steck AK, Rewers M, Norris JM. Association between vitamin D metabolism gene polymorphisms and risk of islet autoimmunity and progression to type 1 diabetes: the diabetes autoimmunity study in the young (DAISY).J Clin Endocrinol Metab. 2013; 98:E1845–E1851.CrossrefMedlineGoogle Scholar
    • 75. Beilfuss J, Berg V, Sneve M, Jorde R, Kamycheva E. Effects of a 1-year supplementation with cholecalciferol on interleukin-6, tumor necrosis factor-alpha and insulin resistance in overweight and obese subjects.Cytokine. 2012; 60:870–874.CrossrefMedlineGoogle Scholar
    • 76. Amer M, Qayyum R. Relation between serum 25-hydroxyvitamin D and C-reactive protein in asymptomatic adults (from the continuous National Health and Nutrition Examination Survey 2001 to 2006).Am J Cardiol. 2012; 109:226–230.CrossrefMedlineGoogle Scholar
    • 77. Hamzaoui K, Ben Dhifallah I, Karray E, Sassi FH, Hamzaoui A. Vitamin D modulates peripheral immunity in patients with Behçet’s disease.Clin Exp Rheumatol. 2010; 28:S50–S57.MedlineGoogle Scholar
    • 78. Raymond MA, Désormeaux A, Labelle A, Soulez M, Soulez G, Langelier Y, Pshezhetsky AV, Hébert MJ. Endothelial stress induces the release of vitamin D-binding protein, a novel growth factor.Biochem Biophys Res Commun. 2005; 338:1374–1382.CrossrefMedlineGoogle Scholar
    • 79. Tarcin O, Yavuz DG, Ozben B, Telli A, Ogunc AV, Yuksel M, Toprak A, Yazici D, Sancak S, Deyneli O, Akalin S. Effect of vitamin D deficiency and replacement on endothelial function in asymptomatic subjects.J Clin Endocrinol Metab. 2009; 94:4023–4030.CrossrefMedlineGoogle Scholar
    • 80. Al Mheid I, Patel R, Murrow J, Morris A, Rahman A, Fike L, Kavtaradze N, Uphoff I, Hooper C, Tangpricha V, Alexander RW, Brigham K, Quyyumi AA. Vitamin D status is associated with arterial stiffness and vascular dysfunction in healthy humans.J Am Coll Cardiol. 2011; 58:186–192.CrossrefMedlineGoogle Scholar
    • 81. Mayer O, Filipovský J, Seidlerová J, Vaněk J, Dolejšová M, Vrzalová J, Cífková R. The association between low 25-hydroxyvitamin D and increased aortic stiffness.J Hum Hypertens. 2012; 26:650–655.CrossrefMedlineGoogle Scholar
    • 82. Giallauria F, Milaneschi Y, Tanaka T, Maggio M, Canepa M, Elango P, Vigorito C, Lakatta EG, Ferrucci L, Strait J. Arterial stiffness and vitamin D levels: the Baltimore longitudinal study of aging.J Clin Endocrinol Metab. 2012; 97:3717–3723.CrossrefMedlineGoogle Scholar
    • 83. Karohl C, Vaccarino V, Veledar E, Goldberg J, Tangpricha V, Bellasi A, Raggi P. Vitamin D status and coronary flow reserve measured by positron emission tomography: a co-twin control study.J Clin Endocrinol Metab. 2013; 98:389–397.CrossrefMedlineGoogle Scholar
    • 84. Dong Y, Stallmann-Jorgensen IS, Pollock NK, Harris RA, Keeton D, Huang Y, Li K, Bassali R, Guo DH, Thomas J, Pierce GL, White J, Holick MF, Zhu H. A 16-week randomized clinical trial of 2000 international units daily vitamin D3 supplementation in black youth: 25-hydroxyvitamin D, adiposity, and arterial stiffness.J Clin Endocrinol Metab. 2010; 95:4584–4591.CrossrefMedlineGoogle Scholar
    • 85. Breslavsky A, Frand J, Matas Z, Boaz M, Barnea Z, Shargorodsky M. Effect of high doses of vitamin D on arterial properties, adiponectin, leptin and glucose homeostasis in type 2 diabetic patients.Clin Nutr. 2013; 32:970–975.CrossrefMedlineGoogle Scholar
    • 86. Yiu YF, Chan YH, Yiu KH, Siu CW, Li SW, Wong LY, Lee SW, Tam S, Wong EW, Cheung BM, Tse HF. Vitamin D deficiency is associated with depletion of circulating endothelial progenitor cells and endothelial dysfunction in patients with type 2 diabetes.J Clin Endocrinol Metab. 2011; 96:E830–E835.CrossrefMedlineGoogle Scholar
    • 87. Talmor Y, Golan E, Benchetrit S, Bernheim J, Klein O, Green J, Rashid G. Calcitriol blunts the deleterious impact of advanced glycation end products on endothelial cells.Am J Physiol Renal Physiol. 2008; 294:F1059–F1064.CrossrefMedlineGoogle Scholar
    • 88. Merke J, Hofmann W, Goldschmidt D, Ritz E. Demonstration of 1,25(OH)2 vitamin D3 receptors and actions in vascular smooth muscle cells in vitro.Calcif Tissue Int. 1987; 41:112–114.CrossrefMedlineGoogle Scholar
    • 89. Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system.J Clin Invest. 2002; 110:229–238.CrossrefMedlineGoogle Scholar
    • 90. Yuan W, Pan W, Kong J, Zheng W, Szeto FL, Wong KE, Cohen R, Klopot A, Zhang Z, Li YC. 1,25-dihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter.J Biol Chem. 2007; 282:29821–29830.CrossrefMedlineGoogle Scholar
    • 91. Cheng Q, Li YC, Boucher BJ, Leung PS. A novel role for vitamin D: modulation of expression and function of the local renin-angiotensin system in mouse pancreatic islets.Diabetologia. 2011; 54:2077–2081.CrossrefMedlineGoogle Scholar
    • 92. Zhou C, Lu F, Cao K, Xu D, Goltzman D, Miao D. Calcium-independent and 1,25(OH)2D3-dependent regulation of the renin-angiotensin system in 1alpha-hydroxylase knockout mice.Kidney Int. 2008; 74:170–179.CrossrefMedlineGoogle Scholar
    • 93. Pilz S, Tomaschitz A, Ritz E, Pieber TR. Vitamin D status and arterial hypertension: a systematic review.Nat Rev Cardiol. 2009; 6:621–630.CrossrefMedlineGoogle Scholar
    • 94. Vaidya A, Forman JP, Hopkins PN, Seely EW, Williams JS. 25-Hydroxyvitamin D is associated with plasma renin activity and the pressor response to dietary sodium intake in Caucasians.J Renin Angiotensin Aldosterone Syst. 2011; 12:311–319.CrossrefMedlineGoogle Scholar
    • 95. Martins D, Wolf M, Pan D, Zadshir A, Tareen N, Thadhani R, Felsenfeld A, Levine B, Mehrotra R, Norris K. Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey.Arch Intern Med. 2007; 167:1159–1165.CrossrefMedlineGoogle Scholar
    • 96. Burgaz A, Orsini N, Larsson SC, Wolk A. Blood 25-hydroxyvitamin D concentration and hypertension: a meta-analysis.J Hypertens. 2011; 29:636–645.CrossrefMedlineGoogle Scholar
    • 97. Waugh JM, Yuksel E, Li J, Kuo MD, Kattash M, Saxena R, Geske R, Thung SN, Shenaq SM, Woo SL. Local overexpression of thrombomodulin for in vivo prevention of arterial thrombosis in a rabbit model.Circ Res. 1999; 84:84–92.CrossrefMedlineGoogle Scholar
    • 98. Aihara K, Azuma H, Akaike M, et al.. Disruption of nuclear vitamin D receptor gene causes enhanced thrombogenicity in mice.J Biol Chem. 2004; 279:35798–35802.CrossrefMedlineGoogle Scholar
    • 99. Stach K, Kälsch AI, Nguyen XD, Elmas E, Kralev S, Lang S, Weiss C, Borggrefe M, Kälsch T. 1α,25-dihydroxyvitamin D3 attenuates platelet activation and the expression of VCAM-1 and MT1-MMP in human endothelial cells.Cardiology. 2011; 118:107–115.CrossrefMedlineGoogle Scholar
    • 100. Hyppönen E, Berry D, Cortina-Borja M, Power C. 25-Hydroxyvitamin D and pre-clinical alterations in inflammatory and hemostatic markers: a cross sectional analysis in the 1958 British Birth Cohort.PLoS One. 2010; 5:e10801.CrossrefMedlineGoogle Scholar
    • 101. Agmon-Levin N, Blank M, Zandman-Goddard G, Orbach H, Meroni PL, Tincani A, Doria A, Cervera R, Miesbach W, Stojanovich L, Barak V, Porat-Katz BS, Amital H, Shoenfeld Y. Vitamin D: an instrumental factor in the anti-phospholipid syndrome by inhibition of tissue factor expression.Ann Rheum Dis. 2011; 70:145–150.CrossrefMedlineGoogle Scholar
    • 102. Brøndum-Jacobsen P, Benn M, Tybjaerg-Hansen A, Nordestgaard BG. 25-Hydroxyvitamin D concentrations and risk of venous thromboembolism in the general population with 18,791 participants.J Thromb Haemost. 2013; 11:423–431.CrossrefMedlineGoogle Scholar
    • 103. Freestone T, Turner RJ, Coady A, Higman DJ, Greenhalgh RM, Powell JT. Inflammation and matrix metalloproteinases in the enlarging abdominal aortic aneurysm.Arterioscler Thromb Vasc Biol. 1995; 15:1145–1151.LinkGoogle Scholar
    • 104. Deng GG, Martin-McNulty B, Sukovich DA, Freay A, Halks-Miller M, Thinnes T, Loskutoff DJ, Carmeliet P, Dole WP, Wang YX. Urokinase-type plasminogen activator plays a critical role in angiotensin II-induced abdominal aortic aneurysm.Circ Res. 2003; 92:510–517.LinkGoogle Scholar
    • 105. Timms PM, Mannan N, Hitman GA, Noonan K, Mills PG, Syndercombe-Court D, Aganna E, Price CP, Boucher BJ. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders?QJM. 2002; 95:787–796.CrossrefMedlineGoogle Scholar
    • 106. Wasse H, Cardarelli F, De Staercke C, Hooper C, Veledar E, Guessous I. 25-hydroxyvitamin D concentration is inversely associated with serum MMP-9 in a cross-sectional study of African American ESRD patients.BMC Nephrol. 2011; 12:24.CrossrefMedlineGoogle Scholar
    • 107. Yao Z, Jaeger JC, Ruzzo WL, Morale CZ, Emond M, Francke U, Milewicz DM, Schwartz SM, Mulvihill ER. A Marfan syndrome gene expression phenotype in cultured skin fibroblasts.BMC Genomics. 2007; 8:319.CrossrefMedlineGoogle Scholar
    • 108. Hinek A, Botney M, Mecham R, Parks W. Inhibition of tropoelastin expression by 1,25-dihdroxyvitamin D3.Connect Tiss Res. 1991; 26:155–166.CrossrefMedlineGoogle Scholar
    • 109. Bendeck MP, Langille BL. Rapid accumulation of elastin and collagen in the aortas of sheep in the immediate perinatal period.Circ Res. 1991; 69:1165–1169.CrossrefMedlineGoogle Scholar
    • 110. Norman P, Moss I, Sian M, Gosling M, Powell J. Maternal and postnatal vitamin D ingestion influences rat aortic structure, function and elastin content.Cardiovasc Res. 2002; 55:369–374.CrossrefMedlineGoogle Scholar
    • 111. van de Luijtgaarden KM, Voûte MT, Hoeks SE, Bakker EJ, Chonchol M, Stolke RJ, Rouwet EV, Verhagen HJ. Vitamin D deficiency may be an independent risk factor for arterial disease.Eur J Vas Endovasc Surg. 2012; 44:301–306.CrossrefMedlineGoogle Scholar
    • 112. Wong YYE, Flicker L, B YB, A MK, Hankey GJ, Norman PE. Is hypovitaminosis D associated with abdominal aortic aneurysm, and is there a dose-response relationship?Eur J Vasc Endovasc Surg2013; 45:657–664.CrossrefMedlineGoogle Scholar
    • 113. Piovesan A, Molineri N, Casasso F, Emmolo I, Ugliengo G, Cesario F, Borretta G. Left ventricular hypertrophy in primary hyperparathyroidism. Effects of successful parathyroidectomy.Clin Endocrinol (Oxf). 1999; 50:321–328.CrossrefMedlineGoogle Scholar
    • 114. Szalay G, Sauter M, Haberland M, Zuegel U, Steinmeyer A, Kandolf R, Klingel K. Osteopontin: a fibrosis-related marker molecule in cardiac remodeling of enterovirus myocarditis in the susceptible host.Circ Res. 2009; 104:851–859.LinkGoogle Scholar
    • 115. Santillán GE, Vazquez G, Boland RL. Activation of a beta-adrenergic-sensitive signal transduction pathway by the secosteroid hormone 1,25-(OH)2-vitamin D3 in chick heart.J Mol Cell Cardiol. 1999; 31:1095–1104.CrossrefMedlineGoogle Scholar
    • 116. Kosecik M, Ertas T. Dilated cardiomyopathy due to nutritional vitamin D deficiency rickets.Pediatr Int. 2007; 49:397–399.CrossrefMedlineGoogle Scholar
    • 117. Agarwal M, Phan A, Willix R, Barber M, Schwarz ER. Is vitamin D deficiency associated with heart failure? A review of current evidence.J Cardiovasc Pharmacol Ther. 2011; 16:354–363.CrossrefMedlineGoogle Scholar
    • 118. Schleithoff SS, Zittermann A, Tenderich G, Berthold HK, Stehle P, Koerfer R. Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial.Am J Clin Nutr. 2006; 83:754–759.CrossrefMedlineGoogle Scholar
    • 119. Witham MD, Crighton LJ, Gillespie ND. The effects of vitamin D supplementation on physical function and quality of life in older patients with heart failure: a randomised controlled trial.Circ Heart Fail. 2010; 3:195–201.LinkGoogle Scholar
    • 120. Liu LC, Voors AA, van Veldhuisen DJ, van der Veer E, Belonje AM, Szymanski MK, Silljé HH, van Gilst WH, Jaarsma T, de Boer RA. Vitamin D status and outcomes in heart failure patients.Eur J Heart Fail. 2011; 13:619–625.CrossrefMedlineGoogle Scholar
    • 121. Towler DA, Demer LL. Thematic series on the pathobiology of vascular calcification.Circ Res. 2011; 108:1378–1380.LinkGoogle Scholar
    • 122. Watson KE, Abrolat ML, Malone LL, Hoeg JM, Doherty T, Detrano R, Demer LL. Active serum vitamin D levels are inversely correlated with coronary calcification.Circulation. 1997; 96:1755–1760.CrossrefMedlineGoogle Scholar
    • 123. Zebger-Gong H, Müller D, Diercke M, Haffner D, Hocher B, Verberckmoes S, Schmidt S, D’Haese PC, Querfeld U. 1,25-Dihydroxyvitamin D3-induced aortic calcifications in experimental uremia: up-regulation of osteoblast markers, calcium-transporting proteins and osterix.J Hypertens. 2011; 29:339–348.CrossrefMedlineGoogle Scholar
    • 124. Niederhoffer N, Bobryshev YV, Lartaud-Idjouadiene I, Giummelly P, Atkinson J. Aortic calcification produced by vitamin D3 plus nicotine.J Vasc Res. 1997; 34:386–398.CrossrefMedlineGoogle Scholar
    • 125. Rodriguez M, Martinez-Moreno JM, Rodríguez-Ortiz ME, Muñoz-Castañeda JR, Almaden Y. Vitamin D and vascular calcification in chronic kidney disease.Kidney Blood Press Res. 2011; 34:261–268.CrossrefMedlineGoogle Scholar
    • 126. Bas A, Lopez I, Perez J, Rodriguez M, Aguilera-Tejero E. Reversibility of calcitriol-induced medial artery calcification in rats with intact renal function.J Bone Miner Res. 2006; 21:484–490.CrossrefMedlineGoogle Scholar
    • 127. Tintut Y, Patel J, Territo M, Saini T, Parhami F, Demer LL. Monocyte/macrophage regulation of vascular calcification in vitro.Circulation. 2002; 105:650–655.LinkGoogle Scholar
    • 128. Li X, Speer MY, Yang H, Bergen J, Giachelli CM. Vitamin D receptor activators induce an anticalcific paracrine program in macrophages: requirement of osteopontin.Arterioscler Thromb Vasc Biol. 2010; 30:321–326.LinkGoogle Scholar
    • 129. Cozzolino M, Bruschetta E, Stucchi A, Ronco C, Cusi D. Role of vitamin D receptor activators in cardio-renal syndromes.Semin Nephrol. 2012; 32:63–69.CrossrefMedlineGoogle Scholar
    • 130. Mathew S, Lund RJ, Chaudhary LR, Geurs T, Hruska KA. Vitamin D receptor activators can protect against vascular calcification.J Am Soc Nephrol. 2008; 19:1509–1519.CrossrefMedlineGoogle Scholar
    • 131. Moe SM. Klotho: a master regulator of cardiovascular disease?Circulation. 2012; 125:2181–2183.LinkGoogle Scholar
    • 132. Hu MC, Shi M, Zhang J, Quiñones H, Griffith C, Kuro-o M, Moe OW. Klotho deficiency causes vascular calcification in chronic kidney disease.J Am Soc Nephrol. 2011; 22:124–136.CrossrefMedlineGoogle Scholar
    • 133. Lim K, Lu TS, Molostvov G, Lee C, Lam FT, Zehnder D, Hsiao LL. Vascular Klotho deficiency potentiates the development of human artery calcification and mediates resistance to fibroblast growth factor 23.Circulation. 2012; 125:2243–2255.LinkGoogle Scholar
    • 134. Wu-Wong JR, Noonan W, Ma J, Dixon D, Nakane M, Bolin AL, Koch KA, Postl S, Morgan SJ, Reinhart GA. Role of phosphorus and vitamin D analogs in the pathogenesis of vascular calcification.J Pharmacol Exp Ther. 2006; 318:90–98.CrossrefMedlineGoogle Scholar
    • 135. Kendrick J, Targher G, Smits G, Chonchol M. 25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey.Atherosclerosis. 2009; 205:255–260.CrossrefMedlineGoogle Scholar
    • 136. Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K, Benjamin EJ, D’Agostino RB, Wolf M, Vasan RS. Vitamin D deficiency and risk of cardiovascular disease.Circulation. 2008; 117:503–511.LinkGoogle Scholar
    • 137. Jorde R, Grimnes G. Vitamin D and metabolic health with special reference to the effect of vitamin D on serum lipids.Prog Lipid Res. 2011; 50:303–312.CrossrefMedlineGoogle Scholar
    • 138. Ponda MP, Huang X, Odeh MA, Breslow JL, Kaufman HW. Vitamin D may not improve lipid levels: a serial clinical laboratory data study.Circulation. 2012; 126:270–277.LinkGoogle Scholar
    • 139. Wang H, Xia N, Yang Y, Peng DQ. Influence of vitamin D supplementation on plasma lipid profiles: a meta-analysis of randomized controlled trials.Lipids Health Dis. 2012; 11:42.CrossrefMedlineGoogle Scholar
    • 140. Kayaniyil S, Vieth R, Retnakaran R, Knight JA, Qi Y, Gerstein HC, Perkins BA, Harris SB, Zinman B, Hanley AJ. Association of vitamin D with insulin resistance and beta-cell dysfunction in subjects at risk for type 2 diabetes.Diabetes Care. 2010; 33:1379–1381.CrossrefMedlineGoogle Scholar
    • 141. Pittas AG, Sun Q, Manson JE, Dawson-Hughes B, Hu FB. Plasma 25-hydroxyvitamin D concentration and risk of incident type 2 diabetes in women.Diabetes Care. 2010; 33:2021–2023.CrossrefMedlineGoogle Scholar
    • 142. Bizzarri C, Pitocco D, Napoli N, Di Stasio E, Maggi D, Manfrini S, Suraci C, Cavallo MG, Cappa M, Ghirlanda G, Pozzilli P; IMDIAB Group. No protective effect of calcitriol on beta-cell function in recent-onset type 1 diabetes: the IMDIAB XIII trial.Diabetes Care. 2010; 33:1962–1963.CrossrefMedlineGoogle Scholar
    • 143. Mitri J, Muraru MD, Pittas AG. Vitamin D and type 2 diabetes: a systematic review.Eur J Clin Nutr. 2011; 65:1005–1015.CrossrefMedlineGoogle Scholar
    • 144. Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25-hydroxyvitamin D and risk of myocardial infarction in men.Arch Int Med. 2008; 168:1174–1180.CrossrefMedlineGoogle Scholar
    • 145. Brøndum-Jacobsen P, Benn M, Jensen GB, Nordestgaard BG. 25-hydroxyvitamin d levels and risk of ischemic heart disease, myocardial infarction, and early death: population-based study and meta-analyses of 18 and 17 studies.Arterioscler Thromb Vasc Biol. 2012; 32:2794–2802.LinkGoogle Scholar
    • 146. Brøndum-Jacobsen P, Nordestgaard BG, Schnohr P, Benn M. 25-hydroxyvitamin D and symptomatic ischemic stroke: an original study and meta-analysis.Ann Neurol. 2013; 73:38–47.CrossrefMedlineGoogle Scholar
    • 147. Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin D levels and the risk of mortality in the general population.Arch Intern Med. 2008; 168:1629–1637.CrossrefMedlineGoogle Scholar
    • 148. Ginde AA, Scragg R, Schwartz RS, Camargo CA. Prospective study of serum 25-hydroxyvitamin D level, cardiovascular disease mortality, and all-cause mortality in older U.S. adults.J Am Geriatr Soc. 2009; 57:1595–1603.CrossrefMedlineGoogle Scholar
    • 149. Skaaby T, Husemoen LL, Pisinger C, Jørgensen T, Thuesen BH, Fenger M, Linneberg A. Vitamin D status and cause-specific mortality: a general population study.PLoS One. 2012; 7:e52423.CrossrefMedlineGoogle Scholar
    • 150. Zittermann A, Iodice S, Pilz S, Grant WB, Bagnardi V, Gandini S. Vitamin D deficiency and mortality risk in the general population: a meta-analysis of prospective cohort studies.Am J Clin Nutr. 2012; 95:91–100.CrossrefMedlineGoogle Scholar
    • 151. Schöttker B, Haug U, Schomburg L, Köhrle J, Perna L, Müller H, Holleczek B, Brenner H. Strong associations of 25-hydroxyvitamin D concentrations with all-cause, cardiovascular, cancer, and respiratory disease mortality in a large cohort study.Am J Clin Nutr. 2013; 97:782–793.CrossrefMedlineGoogle Scholar
    • 152. Semba RD, Houston DK, Bandinelli S, Sun K, Cherubini A, Cappola AR, Guralnik JM, Ferrucci L. Relationship of 25-hydroxyvitamin D with all-cause and cardiovascular disease mortality in older community-dwelling adults.Eur J Clin Nutr. 2010; 64:203–209.CrossrefMedlineGoogle Scholar
    • 153. Wang L, Song Y, Manson JE, Pilz S, März W, Michaëlsson K, Lundqvist A, Jassal SK, Barrett-Connor E, Zhang C, Eaton CB, May HT, Anderson JL, Sesso HD. Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies.Circ Cardiovasc Qual Outcomes. 2012; 5:819–829.LinkGoogle Scholar
    • 154. Melamed ML, Muntner P, Michos ED, Uribarri J, Weber C, Sharma J, Raggi P. Serum 25-hydroxyvitamin D levels and the prevalence of peripheral arterial disease: results from NHANES 2001 to 2004.Arterioscler Thromb Vasc Biol. 2008; 28:1179–1185.LinkGoogle Scholar
    • 155. Gouveri E, Papanas N, Hatzitolios AI, Maltezos E. Hypovitaminosis D and peripheral arterial disease: emerging link beyond cardiovascular risk factors.Eur J Intern Med. 2012; 23:674–681.CrossrefMedlineGoogle Scholar
    • 156. Ogren M, Hedblad B, Engström G, Janzon L. Prevalence and prognostic significance of asymptomatic peripheral arterial disease in 68-year-old men with diabetes. Results from the population study ‘Men born in 1914’ from Malmö, Sweden.Eur J Vasc Endovasc Surg. 2005; 29:182–189.CrossrefMedlineGoogle Scholar
    • 157. Hyde Z, Mylankal KJ, Hankey GJ, Flicker L, Norman PE. Peripheral arterial disease increases the risk of subsequent hip fracture in older men: the Health in Men Study.Osteoporos Int. 2013; 24:1683–1688.CrossrefMedlineGoogle Scholar
    • 158. Shroff R, Egerton M, Bridel M, Shah V, Donald AE, Cole TJ, Hiorns MP, Deanfield JE, Rees L. A bimodal association of vitamin D levels and vascular disease in children on dialysis.J Am Soc Nephrol. 2008; 19:1239–1246.CrossrefMedlineGoogle Scholar
    • 159. Sanders KM, Nicholson GC, Ebeling PR. Is high dose vitamin D harmful?Calcif Tissue Int. 2013; 92:191–206.CrossrefMedlineGoogle Scholar
    • 160. Robinson-Cohen C, Hoofnagle AN, Ix JH, Sachs MC, Tracy RP, Siscovick DS, Kestenbaum BR, de Boer IH. Racial differences in the association of serum 25-hydroxyvitamin D concentration with coronary heart disease events.JAMA. 2013; 310:179–188.CrossrefMedlineGoogle Scholar
    • 161. Freedman BI, Register TC. Effect of race and genetics on vitamin D metabolism, bone and vascular health.Nat Rev Nephrol. 2012; 8:459–466.CrossrefMedlineGoogle Scholar
    • 162. McGreevy C, Williams D. New insights about vitamin D and cardiovascular disease.Ann Int Med. 2011; 155:820–826.CrossrefMedlineGoogle Scholar
    • 163. Jääskeläinen T, Knekt P, Marniemi J, Sares-Jäske L, Männistö S, Heliövaara M, Järvinen R. Vitamin D status is associated with sociodemographic factors, lifestyle and metabolic health.Eur J Nutr. 2013; 52:513–525.CrossrefMedlineGoogle Scholar
    • 164. Levin GP, Robinson-Cohen C, de Boer IH, et al.. Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes.JAMA. 2012; 308:1898–1905.CrossrefMedlineGoogle Scholar
    • 165. Elamin MB, Abu Elnour NO, Elamin KB, Fatourechi MM, Alkatib AA, Almandoz JP, Liu H, Lane MA, Mullan RJ, Hazem A, Erwin PJ, Hensrud DD, Murad MH, Montori VM. Vitamin D and cardiovascular outcomes: a systematic review and meta-analysis.J Clin Endocrinol Metab. 2011; 96:1931–1942.CrossrefMedlineGoogle Scholar
    • 166. Manson JE, Bassuk SS, Lee IM, Cook NR, Albert MA, Gordon D, Zaharris E, Macfadyen JG, Danielson E, Lin J, Zhang SM, Buring JE. The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease.Contemp Clin Trials. 2012; 33:159–171.CrossrefMedlineGoogle Scholar
    • 167. Vidal M, Ramana CV, Dusso AS. Stat1-vitamin D receptor interactions antagonize 1,25-dihydroxyvitamin D transcriptional activity and enhance stat1-mediated transcription.Mol Cell Biol. 2002; 22:2777–2787.CrossrefMedlineGoogle Scholar
    • 168. Picotto G, Liaudat AC, Bohl L, Tolosa de Talamoni N. Molecular aspects of vitamin D anticancer activity.Cancer Invest. 2012; 30:604–614.CrossrefMedlineGoogle Scholar
    • 169. Lundberg AM, Hansson GK. Innate immune signals in atherosclerosis.Clin Immunol. 2010; 134:5–24.CrossrefMedlineGoogle Scholar
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