Vol 31, No 8 | Arteriosclerosis, Thrombosis, and Vascular Biology

Arteriosclerosis, Thrombosis, and Vascular Biology

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1711,

originally publishedAugust 1, 2011,

https://doi.org/10.1161/ATV.0b013e31822a51e2

An 11-μm-Thick Glycocalyx?

It's All in the Technique!

Karen L. de Mesy Bentley

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1712–1713,

originally publishedAugust 1, 2011,

https://doi.org/10.1161/ATVBAHA.111.229849

Steatosis DeLIVERs High-Sensitivity C-Reactive Protein

James P. Luyendyk and
Grace L. Guo

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1714–1715,

originally publishedAugust 1, 2011,

https://doi.org/10.1161/ATVBAHA.111.230722

Triglycerides and Heart Disease

Still a Hypothesis?

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1716–1725,

originally publishedApril 28, 2011,

https://doi.org/10.1161/ATVBAHA.111.226100

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The purpose of this article is to review the basic and clinical science relating plasma triglycerides and cardiovascular disease. Although many aspects of the basic physiology of triglyceride production, its plasma transport, and its tissue uptake have been known for several decades, the relationship of plasma triglyceride levels to vascular disease is uncertain. Are triglyceride-rich lipoproteins, their influence on high-density lipoprotein and low-density lipoprotein, or the underlying diseases that lead to defects in triglyceride metabolism the culprit? Animal models have failed to confirm that anything other than early fatty lesions can be produced by triglyceride-rich lipoproteins. Metabolic products of triglyceride metabolism can be toxic to arterial cells; however, these studies are primarily in vitro. Correlative studies of fasting and postprandial triglycerides and genetic diseases implicate very-low-density lipoprotein and their remnants and chylomicron remnants in atherosclerosis development, but the concomitant alterations in other lipoproteins and other risk factors obscure any conclusions about direct relationships between disease and triglycerides. Genes that regulate triglyceride levels also correlate with vascular disease. Human intervention trials, however, have lacked an appropriately defined population and have produced outcomes without definitive conclusions. The time is more than ripe for new and creative approaches to understanding the relationship of triglycerides and heart disease.

Reverse Cholesterol Transport Revisited

Contribution of Biliary Versus Intestinal Cholesterol Excretion

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1726–1733,

originally publishedMay 12, 2011,

https://doi.org/10.1161/ATVBAHA.108.181206

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Reverse cholesterol transport (RCT) is usually defined as high-density lipoprotein-mediated transport of excess cholesterol from peripheral tissues, including cholesterol-laden macrophages in vessel walls, to the liver. From the liver, cholesterol can then be removed from the body via secretion into the bile for eventual disposal via the feces. According to this paradigm, high plasma high-density lipoprotein levels accelerate RCT and hence are atheroprotective. New insights in individual steps of the RCT pathway, in part derived from innovative mouse models, indicate that the classical concept of RCT may require modification.

Microbial Sensing by Toll Receptors

A Historical Perspective

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1734–1738,

originally publishedAugust 1, 2011,

https://doi.org/10.1161/ATVBAHA.108.179523

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The family of Toll-like receptors plays an essential role in the induction of the immune response. These receptors sense the presence of microbial ligands and activate the nuclear factor-κB transcription factor. We review the key studies that led from the formulation of the concept of pattern recognition receptors to the characterization of Toll-like receptors, insisting on the important role played by the model organism Drosophila melanogaster and on the increasing evidence connecting these receptors to cardiovascular disease.

Response Gene to Complement 32 Promotes Vascular Lesion Formation Through Stimulation of Smooth Muscle Cell Proliferation and Migration

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: e19–e26,

originally publishedJune 2, 2011,

https://doi.org/10.1161/ATVBAHA.111.230706

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Objective—
The objectives of this study were to determine the role of response gene to complement 32 (RGC-32) in vascular lesion formation after experimental angioplasty and to explore the underlying mechanisms.
Methods and Results—
Using a rat carotid artery balloon-injury model, we documented for the first time that neointima formation was closely associated with a significantly increased expression of RGC-32 protein. Short hairpin RNA knockdown of RGC-32 via adenovirus-mediated gene delivery dramatically inhibited the lesion formation by 62% as compared with control groups 14 days after injury. Conversely, RGC-32 overexpression significantly promoted the neointima formation by 33%. Gain- and loss-of-function studies in primary culture of rat aortic smooth muscle cells (RASMCs) indicated that RGC-32 is essential for both the proliferation and migration of RASMCs. RGC-32 induced RASMC proliferation by enhancing p34^CDC2 activity. RGC-32 stimulated the migration of RASMC by inducing focal adhesion contact and stress fiber formation. These effects were caused by the enhanced rho kinase II-α activity due to RGC-32-induced downregulation of Rad GTPase.
Conclusion—
RGC-32 plays an important role in vascular lesion formation following vascular injury. Increased RGC-32 expression in vascular injury appears to be a novel mechanism underlying the migration and proliferation of vascular smooth muscle cells. Therefore, targeting RGC-32 is a potential therapeutic strategy for the prevention of vascular remodeling in proliferative vascular diseases.

Targeted Disruption of the Prostaglandin E₂ E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1739–1747,

originally publishedJune 2, 2011,

https://doi.org/10.1161/ATVBAHA.111.226142

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Objective—
Restenosis after angioplasty remains a major clinical problem. Prostaglandin E₂ (PGE₂) plays an important role in vascular homeostasis. The PGE₂ receptor E-prostanoid 2 (EP2) is involved in the proliferation and migration of various cell types. We aimed to determine the role of EP2 in the pathogenesis of neointimal formation after vascular injury.
Methods and Results—
Wire-mediated vascular injury was induced in the femoral arteries of male wild-type (EP2+/+) and EP2 gene-deficient (EP2−/−) mice. In EP2+/+ mice, EP2 mRNA expression was increased in injured vessels for at least 4 weeks after vascular injury. Neointimal hyperplasia was markedly accelerated in EP2−/− mice, which was associated with increased proliferation and migration of vascular smooth muscle cells (VSMCs) and increased cyclin D1 expression in the neointima layer. Platelet-derived growth factor-BB (PDGF-BB) treatment resulted in more significant cell proliferation and migration in VSMCs of EP2−/− mice than in those of EP2+/+ mice. Activation and overexpression of EP2 attenuated PDGF-BB–elicited cell proliferation and migration, induced G₁→S-phase arrest and reduced PDGF-BB–stimulated extracellular signal–regulated kinase phosphorylation in EP2+/+ VSMCs.
Conclusion—
These findings reveal a novel role of the EP2 receptor in neointimal hyperplasia after arterial injury. The EP2 receptor may represent a potential therapeutic target for restenosis after angioplasty.

Aging Causes Collateral Rarefaction and Increased Severity of Ischemic Injury in Multiple Tissues

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1748–1756,

originally publishedMay 26, 2011,

https://doi.org/10.1161/ATVBAHA.111.227314

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Objective—
Aging is a major risk factor for increased ischemic tissue injury. Whether collateral rarefaction and impaired remodeling contribute to this is unknown. We quantified the number and diameter of native collaterals and their remodeling in 3-, 16-, 24-, and 31-month-old mice.
Methods and Results—
Aging caused an “age-dose-dependent” greater drop in perfusion immediately after femoral artery ligation, followed by a diminished recovery of flow and increase in tissue injury. These effects were associated with a decline in collateral number, diameter, and remodeling. Angiogenesis was also impaired. Mechanistically, these changes were not accompanied by reduced recruitment of T cells or macrophages to remodeling collaterals. However, endothelial nitric oxide synthase signaling was dysfunctional, as indicated by increased protein nitrosylation and less phosphorylated endothelial nitric oxide synthase and vasodilator-stimulated phosphoprotein in collateral wall cells. The cerebral circulation exhibited a similar age-dose-dependent loss of collateral number and diameter and increased tortuosity, resulting in an increase in collateral resistance and infarct volume (eg, 6- and 3-fold, respectively, in 24-month-old mice) after artery occlusion. This was not associated with rarefaction of similarly sized arterioles. Collateral remodeling was also reduced.
Conclusion—
Our findings demonstrate that aging causes rarefaction and insufficiency of the collateral circulation in multiple tissues, resulting in more severe ischemic tissue injury.

Impaired Expression of Uncoupling Protein 2 Causes Defective Postischemic Angiogenesis in Mice Deficient in AMP-Activated Protein Kinase α Subunits

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1757–1765,

originally publishedMay 19, 2011,

https://doi.org/10.1161/ATVBAHA.111.227991

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Objective—
The aim of the present study was to determine whether mitochondrial uncoupling protein (UCP) 2 is required for AMPK-dependent angiogenesis in ischemia in vivo.
Methods and Results—
Angiogenesis was assayed by monitoring endothelial tube formation (a surrogate for angiogenesis) in human umbilical vein endothelial cells (ECs), isolated mouse aortic endothelial cells (MAECs), and pulmonary microvascular endothelial cells or in ischemic thigh adductor muscles from wild-type (WT) mice or mice deficient in either AMPKα1 or AMPKα2. AMPK inhibition with pharmacological inhibitor (compound C) or genetic means (transfection of AMPKα-specific small interfering RNA) significantly lowered the tube formation in human umbilical vein ECs. Consistently, compared with WT mice, tube formation in MAECs isolated from either AMPKα1^−/− or AMPKα2^−/− mice, which exhibited oxidative stress and reduced expression of UCP2, was significantly impaired. In addition, adenoviral overexpression of UCP2, but not adenoviruses encoding green fluorescent protein, normalized tube formation in MAECs from either AMPKα1^−/− or AMPKα2^−/− mice. Similarly, supplementation with sodium nitroprusside, a nitric oxide (NO) donor, restored tube formation. Furthermore, ischemia significantly increased angiogenesis, serine 1177 phosphorylation of endothelial NO synthase, and UCP2 in ischemic thigh adductor muscles from WT mice but not in those from either AMPKα1^−/− or AMPKα2^−/− mice.
Conclusion—
We conclude that AMPK-dependent UCP2 expression in ECs promotes angiogenesis in vivo.

Anoxia-Reoxygenation Enhances Platelet Thromboxane A₂ Production via Reactive Oxygen Species–Generated NOX2

Effect in Patients Undergoing Elective Percutaneous Coronary Intervention

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1766–1771,

originally publishedJune 2, 2011,

https://doi.org/10.1161/ATVBAHA.111.227959

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Objective—
Platelets undergoing anoxia-reoxygenation (AR) simultaneously increase reactive oxygen species (ROS) and thromboxane (Tx) B₂. Our aim was to assess whether there is an interplay between activation of NOX2, the catalytic subunit of NADPH oxidase, and platelet TxB₂ in vitro and in vivo.
Methods and Results—
Platelets that underwent AR had enhanced ROS. This was associated with NOX2 activation and was inhibited by incubation with NOX2-blocking peptide. AR was associated with TxB₂ and isoprostane production, which were inhibited by NOX2-blocking peptide, vitamin C, and the inhibitor of phospholipase A₂. Platelet incubation with 100 μmol/L aspirin fully prevented AR-induced TxA₂ but did not affect isoprostane production. We included 56 aspirin-treated patients undergoing elective percutaneous coronary intervention (PCI) who were randomly allocated to receive either placebo or intravenous infusion of 1 g of vitamin C. Blood TxB₂, isoprostanes, and soluble NOX2-derived peptide, a marker of systemic NADPH oxidase activation, significantly increased at 60 and 120 minutes after PCI in placebo-treated but not in vitamin C-treated patients.
Conclusion—
AR is associated with overproduction of platelet TxB₂ and isoprostanes, which is dependent on NOX2-dependent ROS generation. Low doses of aspirin are unable to prevent TxB₂ formation in patients who undergo PCI.

Dietary α-Linolenic Acid Inhibits Arterial Thrombus Formation, Tissue Factor Expression, and Platelet Activation

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1772–1780,

originally publishedMay 12, 2011,

https://doi.org/10.1161/ATVBAHA.111.226118

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Objective—
Plant-derived α-linolenic acid (ALA) may constitute an attractive cardioprotective alternative to fish-derived n-3 fatty acids. However, the effect of dietary ALA on arterial thrombus formation remains unknown.
Methods and Results—
Male C57Bl/6 mice were fed a high-ALA or low-ALA diet for 2 weeks. Arterial thrombus formation was delayed in mice fed a high-ALA diet compared with those on a low-ALA diet (n=7; P<0.005). Dietary ALA impaired platelet aggregation to collagen and thrombin (n=5; P<0.005) and decreased p38 mitogen-activated protein kinase activation in platelets. Dietary ALA impaired arterial tissue factor (TF) expression, TF activity, and nuclear factor-κB activity (n=7; P<0.05); plasma clotting times and plasma thrombin generation did not differ (n=5; P=not significant). In cultured human vascular smooth muscle and endothelial cells, ALA inhibited TF expression and activity (n=4; P<0.01). Inhibition of TF expression occurred at the transcriptional level via the mitogen-activated protein kinase p38 in smooth muscle cells and p38, extracellular signal-regulated kinases 1 and 2, and c-Jun N-terminal kinases 1 and 2 in endothelial cells.
Conclusion—
ALA impairs arterial thrombus formation, TF expression, and platelet activation and thereby represents an attractive nutritional intervention with direct dual antithrombotic effects.

Multifaceted Role of Plasminogen Activator Inhibitor-1 in Regulating Early Remodeling of Vein Bypass Grafts

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1781–1787,

originally publishedMay 12, 2011,

https://doi.org/10.1161/ATVBAHA.111.228767

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Objective—
The role of plasminogen activator inhibitor-1 (PAI-1) in vein graft (VG) remodeling is undefined. We examined the effect of PAI-1 on VG intimal hyperplasia and tested the hypothesis that PAI-1 regulates VG thrombin activity.
Methods and Results—
VGs from wild-type (WT), Pai1^−/−, and PAI-1-transgenic mice were implanted into WT, Pai1^−/−, or PAI-1-transgenic arteries. VG remodeling was assessed 4 weeks later. Intimal hyperplasia was significantly greater in PAI-1-deficient mice than in WT mice. The proliferative effect of PAI-1 deficiency was retained in vitronectin-deficient mice, suggesting that PAI-1's antiproteolytic function plays a key role in regulating intimal hyperplasia. Thrombin-induced proliferation of PAI-1-deficient venous smooth muscle cells (SMC) was significantly greater than that of WT SMC, and thrombin activity was significantly higher in PAI-1-deficient VGs than in WT VGs. Increased PAI-1 expression, which has been associated with obstructive VG disease, did not increase intimal hyperplasia.
Conclusion—
Decreased PAI-1 expression (1) promotes intimal hyperplasia by pathways that do not require vitronectin and (2) increases thrombin activity in VG. PAI-1 overexpression, although it promotes SMC migration in vitro, did not increase intimal hyperplasia. These results challenge the concept that PAI-1 drives nonthrombotic obstructive disease in VG and suggest that PAI-1's antiproteolytic function, including its antithrombin activity, inhibits intimal hyperplasia.

Sterol Regulatory Element–Binding Protein-1 Determines Plasma Remnant Lipoproteins and Accelerates Atherosclerosis in Low-Density Lipoprotein Receptor–Deficient Mice

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1788–1795,

originally publishedMay 5, 2011,

https://doi.org/10.1161/ATVBAHA.110.219659

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Objective—
Sterol regulatory element–binding protein-1 (SREBP-1) is nutritionally regulated and is known to be a key transcription factor regulating lipogenic enzymes. The goal of this study was to evaluate the roles of SREBP-1 in dyslipidemia and atherosclerosis.
Methods and Results—
Transgenic mice that overexpress SREBP-1c in the liver and SREBP-1-deficient mice were crossed with low-density lipoprotein receptor (LDLR)–deficient mice, and the plasma lipids and atherosclerosis were analyzed. Hepatic SREBP-1c overexpression in LDLR-deficient mice caused postprandial hypertriglyceridemia, increased very-low-density lipoprotein (VLDL) cholesterol, and decreased high-density lipoprotein cholesterol in plasma, which resulted in accelerated aortic atheroma formation. Conversely, absence of SREBP-1 suppressed Western diet–induced hyperlipidemia in LDLR-deficient mice and ameliorated atherosclerosis. In contrast, bone marrow-specific SREBP-1 deficiency did not alter the development of atherosclerosis. The size of nascent VLDL particles secreted from the liver was increased in SREBP-1c transgenic mice and reduced in SREBP-1-deficient mice, accompanied by upregulation and downregulation of phospholipid transfer protein expression, respectively.
Conclusion—
Hepatic SREBP-1c determines plasma triglycerides and remnant cholesterol and contributes to atherosclerosis in hyperlipidemic states. Hepatic SREBP-1c also regulates the size of nascent VLDL particles.

Knockout of Toll-Like Receptor-2 Attenuates Both the Proinflammatory State of Diabetes and Incipient Diabetic Nephropathy

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1796–1804,

originally publishedMay 26, 2011,

https://doi.org/10.1161/ATVBAHA.111.228924

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Objective—
Type 1 diabetes (T1DM) is a proinflammatory state and confers an increased risk for vascular complications. Toll-like receptors (TLR) could participate in diabetic vasculopathies. Whether TLR activation contributes to the proinflammatory state of T1DM and the pathogenesis of diabetic nephropathy remains unknown.
Methods and Results—
We induced T1DM in TLR2 knockout mice (TLR2−/−) and wild-type littermates (C57BL/6J-WT) using streptozotocin (STZ). Fasting blood, peritoneal macrophages, and kidneys were obtained for flow cytometry, Western blot, microscopy, and cytokine assays at 6 and 14 weeks after induction of diabetes. Macrophage TLR2 expression and MyD88-dependent signaling were increased in diabetic mice (WT+STZ) compared with nondiabetic WT mice. These biomarkers were attenuated in diabetic TLR2−/− macrophages. WT+STZ mice showed increased kidney:body weight ratio due to cell hypertrophy, increased albuminuria, decreased kidney nephrin, podocin, and podocyte number and increased transforming growth factor-β and laminin compared with WT mice. Nephrin, podocin, and podocyte number and effacement were restored, and transforming growth factor-β and laminin levels were decreased in TLR2−/−+ STZ mice kidneys versus WT+STZ. Peritoneal and kidney macrophages were predominantly M1 phenotype in WT+STZ mice; this was attenuated in TLR2−/−+STZ mice.
Conclusion—
These data support a role for TLR2 in promoting inflammation and early changes of incipient diabetic nephropathy, in addition to albuminuria and podocyte loss.

Human Aldose Reductase Expression Accelerates Atherosclerosis in Diabetic Apolipoprotein E−/− Mice

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1805–1813,

originally publishedJune 2, 2011,

https://doi.org/10.1161/ATVBAHA.111.226902

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Objective—
There are several pathways that mediate the aberrant metabolism of glucose and that might induce greater vascular damage in the setting of diabetes. The polyol pathway mediated by aldose reductase (AR) has been postulated to be one such pathway. However, it has been reported that AR reduces toxic lipid aldehydes and, under some circumstances, might be antiatherogenic.
Methods and Results—
Atherosclerosis development was quantified in 2 lines of transgenic mice expressing human AR (hAR) crossed on the apolipoprotein E knockout background. The transgenes were used to increase the normally low levels of this enzyme in wild-type mice. Both generalized hAR overexpression and hAR expression via the Tie 2 promoter increased lesion size in streptozotocin diabetic mice. In addition, pharmacological inhibition of AR reduced lesion size.
Conclusion—
Although in some settings AR expression might reduce levels of toxic aldehydes, transgenic expression of this enzyme within the artery wall leads to greater atherosclerosis.

Genetic Susceptibility of the Arterial Wall Is an Important Determinant of Atherosclerosis in C57BL/6 and FVB/N Mouse Strains

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1814–1820,

originally publishedMay 12, 2011,

https://doi.org/10.1161/ATVBAHA.111.229674

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Objective—
How genetic variations among inbred mouse strains translate into differences in atherosclerosis susceptibility is of significant interest for the development of new therapeutic strategies. The objective of the present study was to examine whether genetically controlled arterial wall properties influence atherosclerosis susceptibility in FVB/N (FVB) and C57BL/6 (B6) apolipoprotein E knockout (apoE^−/−) mouse strains.
Methods and Results—
Common carotid artery segments from B6 apoE^−/−, F1 apoE^−/−, and FVB apoE^−/− mice were transplanted to hybrid F1 apoE^−/− mice, which can accept grafts from both parental strains without adaptive immune responses. The mice were fed a high-fat diet, and atherosclerosis was induced in the transplanted artery segments by placement of a perivascular constrictive collar. Artery segments from B6 apoE^−/− mice developed much larger atherosclerotic lesions than artery segments from FVB or F1 apoE^−/− mice. No differences in aortic arch atherosclerosis of the recipient mice were observed between groups.
Conclusion—
Genetically controlled factors acting at the level of the arterial wall are important determinants of atherosclerosis susceptibility in FVB apoE^−/− and B6 apoE^−/− mice.

Vascular Calcification and Aortic Fibrosis

A Bifunctional Role for Osteopontin in Diabetic Arteriosclerosis

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1821–1833,

originally publishedMay 19, 2011,

https://doi.org/10.1161/ATVBAHA.111.230011

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Objective—
Calcification and fibrosis reduce vascular compliance in arteriosclerosis. To better understand the role of osteopontin (OPN), a multifunctional protein upregulated in diabetic arteries, we evaluated contributions of OPN in male low-density lipoprotein receptor (LDLR)−/− mice fed a high-fat diet.
Methods and Results—
OPN had no impact on high-fat diet–induced hyperglycemia, dyslipidemia, or body composition. However, OPN−/−;LDLR−/− mice exhibited an altered time-course of aortic calcium accrual—reduced during initiation but increased with progression—versus OPN+/+;LDLR−/− controls. Collagen accumulation, chondroid metaplasia, and mural thickness were increased in aortas of OPN−/−;LDLR−/− mice. Aortic compliance was concomitantly reduced. Vascular reexpression of OPN (SM22-OPN transgene) reduced aortic Col2A1 and medial chondroid metaplasia but did not affect atherosclerotic calcification, Col1A1 expression, collagen accumulation, or arterial stiffness. Dosing with the proinflammatory OPN fragment SVVYGLR upregulated aortic Wnt and osteogenic gene expression, increased aortic β-catenin, and restored early-phase aortic calcification in OPN−/−;LDLR−/− mice.
Conclusion—
OPN exerts stage-specific roles in arteriosclerosis in LDLR−/− mice. Actions phenocopied by the OPN metabolite SVVYGLR promote osteogenic calcification processes with disease initiation. OPN limits vascular chondroid metaplasia, endochondral mineralization, and collagen accumulation with progression. Complete deficiency yields a net increase in arteriosclerotic disease, reducing aortic compliance and conduit vessel function in LDLR−/− mice.

Apolipoprotein E Mediates Enhanced Plasma High-Density Lipoprotein Cholesterol Clearance by Low-Dose Streptococcal Serum Opacity Factor via Hepatic Low-Density Lipoprotein Receptors In Vivo

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1834–1841,

originally publishedMay 19, 2011,

https://doi.org/10.1161/ATVBAHA.111.224360

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Objective—
Recombinant streptococcal serum opacity factor (rSOF) mediates the in vitro disassembly of human plasma high-density lipoprotein (HDL) into lipid-free apolipoprotein (apo) A-I, a neo-HDL that is cholesterol poor, and a cholesteryl ester–rich microemulsion (CERM) containing apoE. Given the occurrence of apoE on the CERM, we tested the hypothesis that rSOF injection into mice would reduce total plasma cholesterol clearance via apoE-dependent hepatic low-density lipoprotein receptors (LDLR).
Methods and Results—
rSOF (4 μg) injection into wild-type C57BL/6J mice formed neo-HDL, CERM, and lipid-free apoA-I, as observed in vitro, and reduced plasma total cholesterol (−43%, t_1/2=44±18 minutes) whereas control saline injections had a negligible effect. Similar experiments with apoE^−/− and LDLR^−/− mice reduced plasma total cholesterol ≈0% and 20%, respectively. rSOF was potent; injection of 0.18 μg of rSOF produced 50% of maximum reduction of plasma cholesterol 3 hours postinjection, corresponding to a ≈0.5-mg human dose. Most cholesterol was cleared hepatically (>99%), with rSOF treatment increasing clearance by 65%.
Conclusion—
rSOF injection into mice formed a CERM that was cleared via hepatic LDLR that recognize apoE. This reaction could provide an alternative mechanism for reverse cholesterol transport.

Chromobox Protein Homolog 3 Is Essential for Stem Cell Differentiation to Smooth Muscles In Vitro and in Embryonic Arteriogenesis

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1842–1852,

originally publishedJune 9, 2011,

https://doi.org/10.1161/ATVBAHA.111.230110

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Objective—
Smooth muscle cell (SMC) differentiation is a critical process during cardiovascular formation and development, but the underlying molecular mechanism remains unclear.
Methods and Results—
Here we demonstrated that chromobox protein homolog 3 (Cbx3) is crucial for SMC differentiation from stem cells and that the chromodomain and chromoshadow domain of Cbx3 are responsible for Cbx3-induced SMC differentiation. Moreover, we identified that 4 amino acids (165 to 168) within the chromoshadow domain of Cbx3 are key elements for Cbx3 interaction with Dia-1- and Cbx3-induced SMC differentiation. Mechanistically, we found that Cbx3 mediates SMC differentiation through modulating serum response factor (SRF) recruitment to the promoters of SMC genes, in which the interaction between Cbx3 and Dia-1/SRF plays a crucial role in this process. Moreover, our in vivo study demonstrated that the misexpression of Cbx3 within neural crest cells of chick embryos resulted in the death of chick embryos at early stages because of the maldevelopment of branchial arch arteries.
Conclusion—
Our findings suggest that the interaction between Cbx3 and Dia-1/SRF is essential for SMC differentiation from stem cells and for the development of functional cardiovascular system.

Arginase I Attenuates Inflammatory Cytokine Secretion Induced by Lipopolysaccharide in Vascular Smooth Muscle Cells

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1853–1860,

originally publishedMay 26, 2011,

https://doi.org/10.1161/ATVBAHA.111.229302

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Objective—
Inflammation plays an important role in atherosclerosis. Arginase I (Arg I) promotes the proliferation of vascular smooth muscle cells; however, the effect of Arg I on inflammation remains unknown. The present study investigated the role of Arg I in inflammation in vitro and in vivo.
Methods and Results—
Quantitative reverse transcription–polymerase chain reaction and Western blot analysis demonstrated that Arg I inhibited tumor necrosis factor-α production induced by lipopolysaccharide in human aortic smooth muscle cells. Inducible nitric oxide synthase substrate competition and nuclear factor-κB activation were main contributors to lipopolysaccharide-mediated inflammatory cytokine generation. However, Arg I could attenuate the function of inducible nitric oxide synthase and inhibit the subsequent nuclear factor-κB activation, leading to inhibition of tumor necrosis factor-α generation. Furthermore, upregulation of Arg I significantly decreased macrophage infiltration and inflammation in atherosclerotic plaque of rabbits, whereas downregulation of Arg I aggravated these adverse effects.
Conclusion—
The results indicate the antiinflammatory effects of Arg I and suggest an unexpected beneficial role of Arg I in inflammatory disease.

Cdc42 Controls Vascular Network Assembly Through Protein Kinase Cι During Embryonic Vasculogenesis

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1861–1870,

originally publishedJune 9, 2011,

https://doi.org/10.1161/ATVBAHA.111.230144

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Objective—
The goal of this study was to determine the role of Cdc42 in embryonic vasculogenesis and the underlying mechanisms.
Methods and Results—
By using genetically modified mouse embryonic stem (ES) cells, we demonstrate that ablation of the Rho GTPase Cdc42 blocks vascular network assembly during embryoid body (EB) vasculogenesis without affecting endothelial lineage differentiation. Reexpression of Cdc42 in mutant EBs rescues the mutant phenotype, establishing an essential role for Cdc42 in vasculogenesis. Chimeric analysis revealed that the vascular phenotype is caused by inactivation of Cdc42 in endothelial cells rather than surrounding cells. Endothelial cells isolated from Cdc42-null EBs are defective in directional migration and network assembly. In addition, activation of atypical protein kinase Cι (PKCι) is abolished in Cdc42-null endothelial cells, and PKCι ablation phenocopies the vascular abnormalities of the Cdc42-null EBs. Moreover, the inhibitory phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser9 depends on Cdc42 and PKCι, and expression of kinase-dead GSK-3β in Cdc42-null EBs promotes the formation of linear endothelial segments without branches. These results suggest that PKCι and GSK-3β are downstream effectors of Cdc42 during vascular morphogenesis.
Conclusion—
Cdc42 controls vascular network assembly but not endothelial lineage differentiation by activating PKCι during embryonic vasculogenesis.

Aldosterone Regulates Vascular Gene Transcription via Oxidative Stress–Dependent and –Independent Pathways

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1871–1880,

originally publishedMay 26, 2011,

https://doi.org/10.1161/ATVBAHA.111.229070

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Objective—
Aldosterone (Aldo) antagonism prevents cardiovascular mortality by unclear mechanisms. Aldo binds to the mineralocorticoid receptor (MR), a ligand-activated transcription factor, which is expressed in human vascular cells. Here we define the early Aldo-regulated vascular transcriptome and investigate the mechanisms of gene regulation by Aldo in the vasculature that may contribute to vascular disease.
Methods and Results—
Gene expression profiling of Aldo-treated mouse aortas identified 72 genes regulated by Aldo. These genes are overrepresented in Gene Ontology categories involved in vascular function and disease. Quantitative reverse transcription–polymerase chain reaction was used to confirm and further explore mechanisms of vascular gene regulation by Aldo. Aldo-regulated vascular gene expression was inhibited by actinomycin D and MR antagonists supporting a transcriptional MR-dependent mechanism. Aldo regulation of a subset of genes was enhanced in the setting of vascular endothelial denudation and blocked by the free radical scavenger Tempol, supporting synergy between Aldo and vascular injury that is oxidative stress dependent. In the aortic arch, a region predisposed to atherosclerosis, the injury-enhanced genes also demonstrated enhanced expression compared with the descending aorta, both at baseline and after Aldo exposure. Furthermore, the clinically beneficial MR antagonist spironolactone inhibited expression of the identified genes in aortic tissue from humans with atherosclerosis.
Conclusion—
This study defines the Aldo-regulated vascular transcriptome and characterizes a subset of proatherogenic genes with enhanced Aldo-stimulated, oxidative stress–dependent expression in the setting of vascular injury and in areas predisposed to atherosclerosis. Inhibition of MR regulation of these genes may play a role in the protective effects of Aldo antagonists in patients with vascular disease, and these pathways may provide novel drug targets to prevent atherosclerosis in humans.

Inhibition of Pathological Differentiation of Valvular Interstitial Cells by C-Type Natriuretic Peptide

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1881–1889,

originally publishedMay 26, 2011,

https://doi.org/10.1161/ATVBAHA.111.223974

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Objective—
Calcific aortic valve disease is associated with the differentiation of valvular interstitial cells (VICs) to myofibroblast and osteoblast-like cells, particularly in the fibrosa layer of the valve. Previous studies suggested that C-type natriuretic peptide (CNP) protects against calcific aortic valve disease to maintain homeostasis. We aimed to determine whether CNP inhibits VIC pathological differentiation as a mechanism to explain its protective effects.
Methods and Results—
CNP expression was prominent in normal porcine aortic valves, particularly on the ventricular side, but reduced in sclerotic valves concomitant with the appearance of pathological VIC phenotypes in the fibrosa. In vitro, CNP inhibited calcified aggregate formation and bone-related transcript and protein expression by VICs grown in osteogenic conditions. Under myofibrogenic culture conditions, CNP reduced α-smooth muscle actin expression and cell-mediated gel contraction, indicating inhibition of myofibroblast differentiation. Similar to CNP, simvastatin inhibited VIC osteoblast and myofibroblast differentiation in vitro. Strikingly, simvastatin upregulated CNP expression in VICs cultured under myofibrogenic conditions, and small interfering RNA knockdown of natriuretic peptide receptor-b (a CNP receptor) significantly reduced the antifibrotic effect of simvastatin, suggesting that it acts in part via CNP/NPR-B autocrine/paracrine signaling.
Conclusion—
CNP inhibits myofibroblast and osteoblast differentiation of VICs and is responsible in part for inhibition of VIC myofibroblast differentiation by statins, suggesting novel mechanisms to explain the protective effect of CNP and the pleiotropic effects of statins in the aortic valve.

Thioredoxin-Interacting Protein Mediates TRX1 Translocation to the Plasma Membrane in Response to Tumor Necrosis Factor-α

A Key Mechanism for Vascular Endothelial Growth Factor Receptor-2 Transactivation by Reactive Oxygen Species

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1890–1897,

originally publishedJune 2, 2011,

https://doi.org/10.1161/ATVBAHA.111.226340

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Objective—
Thioredoxin-interacting protein (TXNIP) promotes inflammation in endothelial cells (EC) by binding to thioredoxin-1 (TRX1) in a redox-dependent manner. Formation of the TXNIP-TRX1 complex relieves inhibition of the apoptosis signal–regulating kinase 1–c-Jun N-terminal kinase–vascular cell adhesion molecule-1 pathway. Because TXNIP is an α-arrestin with numerous protein-protein interacting domains, we hypothesized that TXNIP-TRX1 trafficking should alter function of EC exposed to reactive oxygen species (ROS).
Methods and Results—
In response to physiological levels of ROS (10 ng/mL tumor necrosis factor-α and 30 μmol/L H₂O₂), TXNIP-TRX1 translocated to the plasma membrane in human umbilical vein EC, with a peak at 30 minutes, as measured by immunofluorescence colocalization with vascular endothelial-cadherin, cell fractionation, and membrane sheet assay. TXNIP-mediated translocation of TRX1 to the membrane required TXNIP and TRX1 binding, as evidenced by inability of the ROS-insensitive TXNIP-Cys247Ser mutant to promote membrane localization. Vascular endothelial growth factor signaling required TXNIP, as shown by significant decreases in plasma membrane tyrosine phosphorylation and EC migration after TRX1 knockdown. Furthermore, TXNIP knockdown increased human umbilical vein EC apoptosis induced by tumor necrosis factor. Rescue with TXNIP-wild-type but not TXNIP-Cys247Ser prevented cell death.
Conclusion—
These findings suggest a novel role for the TXNIP-TRX1 complex to enable inflammation by promoting EC survival and vascular endothelial growth factor signaling under conditions of physiological oxidative stress.

Endothelial Microparticle Formation by Angiotensin II Is Mediated via Ang II Receptor Type I/NADPH Oxidase/ Rho Kinase Pathways Targeted to Lipid Rafts

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1898–1907,

originally publishedMay 19, 2011,

https://doi.org/10.1161/ATVBAHA.110.222703

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Objective—
Circulating microparticles are increased in cardiovascular disease and may themselves promote oxidative stress and inflammation. Molecular mechanisms underlying their formation and signaling are unclear. We investigated the role of reactive oxygen species (ROS), Rho kinase, and lipid rafts in microparticle formation and examined their functional significance in endothelial cells (ECs).
Methods and Results—
Microparticle formation from angiotensin II (Ang II)–stimulated ECs and apolipoprotein E^−/− mice was assessed by annexin V or by CD144 staining and electron microscopy. Ang II promoted microparticle formation and increased EC
generation and Rho kinase activity. Ang II–stimulated effects were inhibited by irbesartan (Ang II receptor type I blocker) and fasudil (Rho kinase inhibitor). Methyl-β-cyclodextrin and nystatin, which disrupt lipid rafts/caveolae, blocked microparticle release. Functional responses, assessed in microparticle-stimulated ECs, revealed increased
production, enhanced vascular cell adhesion molecule/platelet-EC adhesion molecule expression, and augmented macrophage adhesion. Inhibition of epidermal growth factor receptor blocked the prooxidative and proinflammatory effects of microparticles. In vitro observations were confirmed in apolipoprotein E^−/− mice, which displayed vascular inflammation and high levels of circulating endothelial microparticles, effects that were reduced by apocynin.
Conclusion—
We demonstrated direct actions of Ang II on endothelial microparticle release, mediated through NADPH oxidase, ROS, and Rho kinase targeted to lipid rafts. Microparticles themselves stimulated endothelial ROS formation and inflammatory responses. Our findings suggest a feedforward system whereby Ang II promotes EC injury through its own endothelial-derived microparticles.

Imaging the Endothelial Glycocalyx In Vitro by Rapid Freezing/Freeze Substitution Transmission Electron Microscopy

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1908–1915,

originally publishedApril 7, 2011,

https://doi.org/10.1161/ATVBAHA.111.225268

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Objective—
Recent publications questioned the validity of endothelial cell (EC) culture studies of glycocalyx (GCX) function because of findings that GCX in vitro may be substantially thinner than GCX in vivo. The assessment of thickness differences is complicated by GCX collapse during dehydration for traditional electron microscopy. We measured in vitro GCX thickness using rapid freezing/freeze substitution (RF/FS) transmission electron microscopy (TEM), taking advantage of the high spatial resolution provided by TEM and the capability to stably preserve the GCX in its hydrated configuration by RF/FS.
Methods and Results—
Bovine aortic EC (BAEC) and rat fat pad EC were subjected to conventional or RF/FS-TEM. Conventionally preserved BAEC GCX was ≈0.040 μm in thickness. RF/FS-TEM revealed impressively thick BAEC GCX of ≈11 μm and rat fat pad EC GCX of ≈5 μm. RF/FS-TEM also discerned GCX structure and thickness variations due to heparinase III enzyme treatment and extracellular protein removal, respectively. Immunoconfocal studies confirmed that the in vitro GCX is several micrometers thick and is composed of extensive and well-integrated heparan sulfate, hyaluronic acid, and protein layers.
Conclusion—
New observations by RF/FS-TEM reveal substantial GCX layers on cultured EC, supporting their continued use for fundamental studies of GCX and its function in the vasculature.

An Increased Burden of Common and Rare Lipid-Associated Risk Alleles Contributes to the Phenotypic Spectrum of Hypertriglyceridemia

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1916–1926,

originally publishedMay 19, 2011,

https://doi.org/10.1161/ATVBAHA.111.226365

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Objective—
Earlier studies have suggested that a common genetic architecture underlies the clinically heterogeneous polygenic Fredrickson hyperlipoproteinemia (HLP) phenotypes defined by hypertriglyceridemia (HTG). Here, we comprehensively analyzed 504 HLP-HTG patients and 1213 normotriglyceridemic controls and confirmed that a spectrum of common and rare lipid-associated variants underlies this heterogeneity.
Methods and Results—
First, we demonstrated that genetic determinants of plasma lipids and lipoproteins, including common variants associated with plasma triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) from the Global Lipids Genetics Consortium were associated with multiple HLP-HTG phenotypes. Second, we demonstrated that weighted risk scores composed of common TG-associated variants were distinctly increased across all HLP-HTG phenotypes compared with controls; weighted HDL-C and LDL-C risk scores were also increased, although to a less pronounced degree with some HLP-HTG phenotypes. Interestingly, decomposition of HDL-C and LDL-C risk scores revealed that pleiotropic variants (those jointly associated with TG) accounted for the greatest difference in HDL-C and LDL-C risk scores. The APOE E2/E2 genotype was significantly overrepresented in HLP type 3 versus other phenotypes. Finally, rare variants in 4 genes accumulated equally across HLP-HTG phenotypes.
Conclusion—
HTG susceptibility and phenotypic heterogeneity are both influenced by accumulation of common and rare TG-associated variants.

A Detailed Cardiovascular Characterization of Obesity Without the Metabolic Syndrome

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: e27–e34,

originally publishedMay 5, 2011,

https://doi.org/10.1161/ATVBAHA.110.221572

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Objective—
Although obesity without metabolic disturbances has been regarded as harmless, we have recently shown that obese subjects without the metabolic syndrome (MetS) has an increased risk of cardiovascular (CV) disorders and mortality during long-term follow-up. To investigate the basis for that increased risk, we studied the impact of obesity without MetS on multiple markers of subclinical CV disease.
Methods and Results—
At age 70, 1016 subjects were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors study. According to body mass index (BMI)/MetS status, they were categorized as normal weight (BMI <25 kg/m²) without MetS (National Cholesterol Education Program criteria, n=319), normal weight with MetS (n=19), overweight (BMI 25 to 29.9 kg/m²) without MetS (n=333), overweight with MetS (n=94), obese (BMI ≥30 kg/m²) without MetS (n=102), and obese with MetS (n=118). Several different measurements of endothelial reactivity, arterial compliance (plethysmography and ultrasound), carotid artery atherosclerosis, and echocardiography were performed, and 7 markers of coagulation/fibrinolysis were measured. Subjects with obesity without MetS showed impaired vasoreactivity, a more echolucent carotid artery wall, increased left ventricular mass and function together with impaired coagulation/fibrinolysis compared with normal-weight subjects without the MetS (P<0.05 to 0.001). The majority of these disturbances were also seen in overweight subjects without the MetS.
Conclusion—
In contrast to some previous studies, our data do not support that obesity without MetS is a benign condition, because obesity without MetS was associated with impairments in multiple markers of subclinical CV disease. This was also the case for overweight subjects without the MetS.

Hepatic Steatosis, Obesity, and the Metabolic Syndrome Are Independently and Additively Associated With Increased Systemic Inflammation

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1927–1932,

originally publishedMay 5, 2011,

https://doi.org/10.1161/ATVBAHA.111.228262

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Objective—
The goal of this study was to assess the independent and collective associations of hepatic steatosis, obesity, and the metabolic syndrome with elevated high-sensitivity C-reactive protein (hs-CRP) levels.
Methods and Results—
We evaluated 2388 individuals without clinical cardiovascular disease between December 2004 and December 2006. Hepatic steatosis was diagnosed by ultrasound, and the metabolic syndrome was defined using National Heart, Lung, and Blood Institute criteria. The cut point of ≥3 mg/L was used to define high hs-CRP. Multivariate logistic regression was used to assess the independent and collective associations of hepatic steatosis, obesity, and the metabolic syndrome with high hs-CRP. Steatosis was detected in 32% of participants, 23% met criteria for metabolic syndrome, and 17% were obese. After multivariate regression, hepatic steatosis (odds ratio [OR] 2.07; 95% CI 1.68 to 2.56), obesity (OR 3.00; 95% CI 2.39 to 3.80), and the metabolic syndrome (2.39; 95% CI 1.88 to 3.04) were all independently associated with high hs-CRP. Combinations of these factors were associated with an additive increase in the odds of high hs-CRP, with individuals with 1, 2, and 3 factors having ORs for high hs-CRP of 1.92 (1.49 to 2.48), 3.38 (2.50 to 4.57), and 4.53 (3.23 to 6.35), respectively.
Conclusion—
Hepatic steatosis, obesity, and the metabolic syndrome are independently and additively associated with increased odds of high hs-CRP levels.

Retinal Arteriolar Tortuosity and Cardiovascular Risk Factors in a Multi-Ethnic Population Study of 10-Year-Old Children; the Child Heart and Health Study in England (CHASE)

Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 | Volume 31, Issue 8: 1933–1938,

originally publishedJune 9, 2011,

https://doi.org/10.1161/ATVBAHA.111.225219

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Objective—
To examine the association between cardiovascular risk factors and retinal arteriolar tortuosity in a multi-ethnic child population.
Methods and Results—
Cross sectional study of 986 UK primary school children of South Asian, black African Caribbean, and white European origin aged 10 to 11 years. Anthropometric measurements and retinal imaging were carried out and a fasting blood sample collected. Digital images of retinal arterioles were analyzed using a validated semiautomated measure of tortuosity. Associations between tortuosity and cardiometabolic risk factors were analyzed using multi-level linear regression, adjusted for gender, age, ethnicity, arteriole branch status, month, and school. Levels of arteriolar tortuosity were similar in boys and girls and in different ethnic groups. Retinal arteriolar tortuosity was positively associated with levels of triglyceride, total and LDL cholesterol, and systolic and diastolic blood pressure. One standard deviation increases in these risk factors were associated with 3.7% (95% CI: 1.2%, 6.4%), 3.3% (0.9%, 5.8%), 3.1% (0.6%, 5.6%), 2.0% (−0.3%, 4.2%), and 2.3% (0.1%, 4.6%) increases in tortuosity, respectively. Adiposity, insulin resistance, and blood glucose showed no associations with tortuosity.
Conclusion—
Established cardiovascular risk factors, strongly linked to coronary heart disease in adulthood, may influence retinal arteriolar tortuosity at the end of the first decade of life.

Table of Contents

Editorial Board

Arteriosclerosis, Thrombosis, and Vascular Biology

Editorials

An 11-μm-Thick Glycocalyx?

It's All in the Technique!

Steatosis DeLIVERs High-Sensitivity C-Reactive Protein

Brief Review

Triglycerides and Heart Disease

Still a Hypothesis?

ATVB in Focus: HDL Structure, Function, Therapeutics, and Imaging

Reverse Cholesterol Transport Revisited

Contribution of Biliary Versus Intestinal Cholesterol Excretion

History of Discovery

Microbial Sensing by Toll Receptors

A Historical Perspective

Integrative Physiology and Experimental Medicine

Response Gene to Complement 32 Promotes Vascular Lesion Formation Through Stimulation of Smooth Muscle Cell Proliferation and Migration

Objective—

Methods and Results—

Conclusion—

Targeted Disruption of the Prostaglandin E2 E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice

Objective—

Methods and Results—

Conclusion—

Aging Causes Collateral Rarefaction and Increased Severity of Ischemic Injury in Multiple Tissues

Objective—

Methods and Results—

Conclusion—

Impaired Expression of Uncoupling Protein 2 Causes Defective Postischemic Angiogenesis in Mice Deficient in AMP-Activated Protein Kinase α Subunits

Objective—

Methods and Results—

Conclusion—

Anoxia-Reoxygenation Enhances Platelet Thromboxane A2 Production via Reactive Oxygen Species–Generated NOX2

Effect in Patients Undergoing Elective Percutaneous Coronary Intervention

Objective—

Methods and Results—

Conclusion—

Dietary α-Linolenic Acid Inhibits Arterial Thrombus Formation, Tissue Factor Expression, and Platelet Activation

Objective—

Methods and Results—

Conclusion—

Multifaceted Role of Plasminogen Activator Inhibitor-1 in Regulating Early Remodeling of Vein Bypass Grafts

Objective—

Methods and Results—

Conclusion—

Sterol Regulatory Element–Binding Protein-1 Determines Plasma Remnant Lipoproteins and Accelerates Atherosclerosis in Low-Density Lipoprotein Receptor–Deficient Mice

Objective—

Methods and Results—

Conclusion—

Knockout of Toll-Like Receptor-2 Attenuates Both the Proinflammatory State of Diabetes and Incipient Diabetic Nephropathy

Objective—

Methods and Results—

Conclusion—

Human Aldose Reductase Expression Accelerates Atherosclerosis in Diabetic Apolipoprotein E−/− Mice

Objective—

Methods and Results—

Conclusion—

Genetic Susceptibility of the Arterial Wall Is an Important Determinant of Atherosclerosis in C57BL/6 and FVB/N Mouse Strains

Objective—

Methods and Results—

Conclusion—

Vascular Calcification and Aortic Fibrosis

A Bifunctional Role for Osteopontin in Diabetic Arteriosclerosis

Objective—

Methods and Results—

Conclusion—

Apolipoprotein E Mediates Enhanced Plasma High-Density Lipoprotein Cholesterol Clearance by Low-Dose Streptococcal Serum Opacity Factor via Hepatic Low-Density Lipoprotein Receptors In Vivo

Objective—

Methods and Results—

Conclusion—

Cell Biology/Signaling

Chromobox Protein Homolog 3 Is Essential for Stem Cell Differentiation to Smooth Muscles In Vitro and in Embryonic Arteriogenesis

Objective—

Methods and Results—

Conclusion—

Arginase I Attenuates Inflammatory Cytokine Secretion Induced by Lipopolysaccharide in Vascular Smooth Muscle Cells

Objective—

Methods and Results—

Conclusion—

Targeted Disruption of the Prostaglandin E₂ E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice

Anoxia-Reoxygenation Enhances Platelet Thromboxane A₂ Production via Reactive Oxygen Species–Generated NOX2