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Originally Published 7 January 2019
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CT-1 (Cardiotrophin-1)-Gal-3 (Galectin-3) Axis in Cardiac Fibrosis and Inflammation: Mechanistic Insights and Clinical Implications

Ernesto Martínez-Martínez, Cristina Brugnolaro, Jaime Ibarrola, Susana Ravassa, Mathieu Buonafine, Begoña López, Amaya Fernández-Celis, … Show All … , Ramón Querejeta, Enrique Santamaria, Joaquín Fernández-Irigoyen, Gregorio Rábago, María U Moreno, Frédéric Jaisser, Javier Díez, Arantxa González [email protected], and Natalia López-Andrés [email protected]Author Info & Affiliations
Hypertension
Volume 73, Number 3
https://doi.org/10.1161/HYPERTENSIONAHA.118.11874
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Abstract

Myocardial fibrosis is a main contributor to the development of heart failure (HF). CT-1 (cardiotrophin-1) and Gal-3 (galectin-3) are increased in HF and associated with myocardial fibrosis. The aim of this study is to analyze whether CT-1 regulates Gal-3. Proteomic analysis revealed that Gal-3 was upregulated by CT-1 in human cardiac fibroblasts in parallel with other profibrotic and proinflammatory markers. CT-1 upregulation of Gal-3 was mediated by ERK (extracellular signal-regulated kinase) 1/2 and Stat-3 (signal transducer and activator of transcription 3) pathways. Male Wistar rats and B6CBAF1 mice treated with CT-1 (20 µg/kg per day) presented higher cardiac Gal-3 levels and myocardial fibrosis. In CT-1–treated rats, direct correlations were found between cardiac CT-1 and Gal-3 levels, as well as between Gal-3 and perivascular fibrosis. Gal-3 genetic disruption in human cardiac fibroblasts and pharmacological Gal-3 inhibition in mice prevented the profibrotic and proinflammatory effects of CT-1. Dahl salt-sensitive hypertensive rats with diastolic dysfunction showed increased cardiac CT-1 and Gal-3 expression together with cardiac fibrosis and inflammation. CT-1 and Gal-3 directly correlated with myocardial fibrosis. In HF patients, myocardial and plasma CT-1 and Gal-3 were increased and directly correlated. In addition, HF patients with high CT-1 and Gal-3 plasma levels presented an increased risk of cardiovascular death. Our data suggest that CT-1 upregulates Gal-3 which, in turn, mediates the proinflammatory and profibrotic myocardial effects of CT-1. The elevation of both molecules in HF patients identifies a subgroup of patients with a higher risk of cardiovascular mortality. The CT-1/Gal-3 axis emerges as a candidate therapeutic target and a potential prognostic biomarker in HF.

Introduction

Heart failure (HF) is a chronic cardiovascular condition associated with high morbidity and mortality.1 Myocardial fibrosis plays a major role in the development and evolution of HF.2 Myocardial fibrosis is defined by an increase in extracellular matrix (ECM) deposition and excessive collagen accumulation in the interstitial and perivascular spaces. There is an increasing body of evidence indicating that in the development of HF, namely with preserved ejection fraction, there is an initial phase of systemic and cardiac inflammation which can lead to interstitial and perivascular fibrosis.3 Myocardial fibrosis in HF patients has been shown to be associated with increased left ventricular (LV) stiffness,4 both diastolic5 and systolic dysfunction,6 and a higher risk for hospitalization and cardiovascular death.7 Of note, although HF therapies improve clinical symptoms, fibrosis remains in the myocardium of optimally-treated HF patients.
CT-1 (cardiotrophin-1) is a member of the IL (interleukin)-6 superfamily of proinflammatory cytokines which is expressed in different tissues including heart and vessels.8 CT-1 is elevated in the myocardium9 and plasma9 of HF patients, and it has been shown to be associated with hypertension, cardiac hypertrophy, and fibrosis both in patients9–11 and experimental models.12 Of note, CT-1 is upregulated in cardiac fibroblasts and cardiomyocytes in response to mechanical, humoral, metabolic, and hypoxic stress.13
Gal-3 (galectin-3) is a member of a β-galactoside–binding lectin family which is expressed in inflammatory cells,14 cardiac and vascular cells,15–17 kidney,18 and adipose tissue. Gal-3 levels are increased in the myocardium19 and plasma20 of HF patients, and its levels correlate with some serum ECM markers.20 Previous studies in experimental models have demonstrated that Gal-3 plays a role in inflammation and fibrosis in different pathologies, such as hypertension, obesity, hyperaldosteronism, and pressure overload through its profibrotic and proinflammatory properties.15,16,21
Although CT-1 and Gal-3 are both upregulated by aldosterone through mineralocorticoid receptor activation,22,23 and seem to share profibrotic mechanisms,24 there are not reported data on the interaction between them. We have thus investigated whether CT-1 regulates Gal-3 and whether Gal-3 may mediate the proinflammatory and profibrotic myocardial effects of CT-1. For this purpose, a proteomic approach was used to characterize proteostasis alteration in human cardiac fibroblasts (HCFs) exposed to CT-1. In addition, the interaction between CT-1 and Gal-3, as well as its effects on cardiac remodeling, was analyzed in vitro in HCFs and in vivo in 3 different animal models, including hypertensive rats with HF and diastolic dysfunction. Finally, in patients with HF of hypertensive cause, the associations of CT-1 and Gal-3 at the myocardial and circulating levels, as well as the impact of their combination on the clinical outcome have been evaluated.

Materials and Methods

Data available on request from the authors.
Detailed methods are available in the online-only Data Supplement.

In Vitro Experimental Studies

Adult HCFs were stimulated with CT-1 (10-9–10-7 M). Mass spectrometry-based quantitative proteomics was performed using iTRAQ. Results were validated by real-time polymerase chain reaction, Western blot, and ELISA.

In Vivo Experimental Studies

Rats and Mice Treated With CT-1

Wistar rats and wild-type B6CBAF1 mice were treated with rat recombinant CT-1 (20 µg/kg per day, IP). Half of the mice received the Gal-3 activity inhibitor, modified citrus pectin (100 mg/kg per day). Experiments were approved by the Darwin ethics committee of Pierre et Marie Curie University and conducted according to the INSERM (l'Institut national de la santé et de la recherche médicale) animal care and use committee guidelines.

Dahl Salt-Sensitive Hypertensive Rats

Dahl salt-sensitive rats (SS/JrHsdMcwiCrl) receiving a high-salt diet (8%) developed signs and symptoms of HF and diastolic dysfunction. The experimental protocol was approved by the Ethics Committee of the University of Navarra and conducted according to the University of Navarra Animal Care and Use Committee guidelines.

Clinical Studies

All of the subjects gave written informed consent to participate in the study, and the institutional review Committees approved the study protocols. The study conformed to the principles of the Helsinki Declaration. Two cohorts of 24 and 236 HF patients of hypertensive origin, respectively, were studied.

Statistical Analyses

Data for experimental models are expressed as mean±SEM. Normality of distributions was verified by means of the Kolmogorov-Smirnov test. Data were analyzed using Student t test or the Mann-Whitney U test for the analysis of differences between 2 groups and a 1-way ANOVA, followed by a Newman-Keuls to assess specific differences among several groups or conditions Log transformation was applied to normalize variable’s distribution when needed. Pearson correlation coefficients were calculated to determine correlations. Regarding the analysis of patients, outcome data are expressed as mean±SD. Linear tests for trend were used to assess any tendency across the different groups. Multivariable linear regression models were used to assess the independent relationship between continuous variables. The ability of CT-1 and Gal-3 to identify cardiovascular death was analyzed by receiver operating characteristic curves. The cumulative incidence and the hazard ratios of the considered outcome were obtained by multivariable competing risk models, considering all-cause death as a competing event (for details on the models see the online-only Data Supplement).
Analysis was performed using GraphPad Software, Inc, SPSS (15.0 version) and STATA (12.1 version). The predetermined significance level was a 2-sided P<0.05.

Results

CT-1 Upregulates Gal-3 in Adult HCFs

To obtain a deep insight into the proteostasis modulation induced by CT-1 on HCFs, a shotgun proteome analysis was performed. CT-1 induced protein expression changes in 89 proteins after 24 hours of treatment. Among these proteins, 54 were upregulated, and 35 were downregulated by CT-1.
Among the upregulated proteins, Gal-3 was verified by polymerase chain reaction, Western blot, and ELISA. CT-1 stimulation enhanced (P<0.05) mRNA Gal-3 levels, as well as intracellular protein expression (P<0.05) of Gal-3 in a dose-dependent manner (Figure 1A). CT-1 also induced a dose-dependent increase (P<0.05) in the ECM proteins α-SMA (α-smooth muscle actin), vimentin, and the profibrotic mediators CTGF (connective tissue growth factor), TGF-β (transforming growth factor-β), and OPN (osteopontin; Figure 1A). CT-1 increased the secretion of Gal-3, collagen type I, as well as the proinflammatory markers IL-6, CCL-2 (monocyte chemotactic protein 1), and IL-1β in HCFs (Figure 1B).
Figure 1. Effects of CT-1 (cardiotrophin-1) on Gal-3 (galectin-3), extracellular matrix proteins and inflammatory markers in human cardiac fibroblasts. CT-1 dose-response (10-9–10-7 M) in human cardiac fibroblasts on (A) mRNA Gal-3 levels and intracellular Gal-3, α-SMA (α-smooth muscle actin), vimentin, CTGF (connective tissue growth factor), TGF-β (transforming growth factor-β), and OPN (osteopontin) protein expressions; (B) Gal-3, collagen type I, IL (interleukin)-6, and CCL-2 (monocyte chemotactic protein 1) extracellular protein levels (C) Effects of CT-1 (10-7 M) on intracellular pathways in human cardiac fibroblasts. D, Effects of CT-1 cell signaling chemical inhibitors on Gal-3 expression. E, Effects of CT-1 on mRNA Gal-3 levels, and Gal-3, vimentin, CTGF, and OPN protein levels in Gal-3-silenced human cardiac fibroblasts. F, Effects of CT-1 on collagen type I, IL-6, and CCL-2 extracellular protein levels in Gal-3-silenced human cardiac fibroblasts. Histogram bars represent the mean±SEM of the 3 independent experiments. Densitometry values were normalized to stain-free gel. *P<0.05 vs control. $P<0.05 vs CT-1. Akt indicates protein kinase B; AU, arbitrary units; Col I, collagen type I; MAPK, mitogen-activated protein kinases; NFκB, nuclear factor κB; and siRNA, small-interfering RNA.
The possible intracellular mechanism by which CT-1 upregulates Gal-3 in HCFs was studied. CT-1 induced the phosphorylation of ERK (extracellular signal-regulated kinase) 1/2 (at 10 minutes of stimulation; P<0.05), p38 MAPK (mitogen-activated protein kinases; at 10 minutes of stimulation; P<0.05), NFκB (nuclear factor κB; at 5, 10, and 30 minutes of stimulation; P<0.05), and Stat-3 (signal transducer and activator of transcription 3; at 30 minutes of stimulation; P<0.05; Figure 1C) without modifications in the phosphorylation level of Akt (protein kinase B) and ERK-5 (Figure 1C). The specific inhibitor of ERK 1/2, PD98059, and the specific inhibitor of Stat-3, AG490, were able to prevent the increase in Gal-3 protein levels in cells treated with CT-1 (P<0.05; Figure 1D). In contrast, the pretreatment with the specific inhibitor of p38 MAPK, SB203580, or the specific inhibitor of NFκB, BAY 11–7082, was not able to modify Gal-3 levels after CT-1 treatment (Figure 1D).
In order to investigate the potential involvement of Gal-3 in CT-1 effects in HCFs, Gal-3 silencing was used. Gal-3 siRNA (small-interfering RNA) significantly reduced Gal-3 mRNA and protein levels as compared to controls (P<0.05; Figure 1E). CT-1 treatment did not modify Gal-3 levels in Gal-3–knocked down cells (Figure 1E). In Gal-3 silenced cells, CT-1 did not increase the expression of vimentin without modifications in CTGF or OPN levels (Figure 1E). In addition, CT-1 did not increase the secretion of collagen type I or the proinflammatory markers IL-6 and CCL-2 in Gal-3–silenced-cells (Figure 1F).

CT-1 Upregulates Myocardial Gal-3 in Rodents

CT-1–treated normotensive Wistar rats presented increased myocardial mRNA (P<0.05) and protein (P<0.05) levels of Gal-3 as compared to controls (Figure 2A). This effect was confirmed by immunohistochemistry (Figure S1A in the online-only Data Supplement). As previously reported, CT-1–treated rats presented an increase in perivascular fibrosis as compared to control rats.12 Direct correlations were found between myocardial CT-1 protein and myocardial Gal-3 protein (P<0.01; Figure S1B). Perivascular fibrosis was also correlated with myocardial Gal-3 protein levels (P<0.01; Figure S1C). CT-1–treated rats presented a slight increase, but not significant, in the phosphorylation of Stat-3 and ERK 1/2 (Figure 2B). Interestingly, CT-1–treated rats presented an increase in inflammatory markers CD68, CD80, and CD86 (Figure S1D).
Figure 2. Gal-3 (galectin-3) inhibition blocked CT-1 (cardiotrophin-1) profibrotic and proinflammatory effects. CT-1 effects in rats on (A) Gal-3 mRNA and protein levels; (B) Stat-3 (signal transducer and activator of transcription 3) and ERK (extracellular signal-regulated kinase) 1/2 phosphorylation. Effects of pharmacological inhibition of Gal-3 with modified citrus pectin (MCP) in CT-1–treated mice on (C) Gal-3 mRNA and protein levels; (D) α-SMA (α-smooth muscle actin), vimentin, TGF-β (transforming growth factor-β), CTGF (connective tissue growth factor), and OPN (osteopontin) protein expressions; (E) collagen type I, IL (interleukin)-6, IL-1β, and CCL-2 (monocyte chemotactic protein 1) protein expressions; (F) Stat-3 and ERK 1/2 phosphorylation in CT-1–treated mice. Histogram bars represent the mean±SEM of the 3 independent experiments. Densitometry values were normalized to β-actin or stain-free gel for cDNA and protein respectively. *P<0.05 vs Control. $P<0.05 vs CT-1. AU indicates arbitrary units.
CT-1–treated mice presented LV hypertrophy, as shown by increased LV mass corrected by body weight (P<0.01; Table S1). CT-1–treated mice presented interstitial and perivascular fibrosis (Figure S2). In addition, CT-1 increased myocardial Gal-3 mRNA and protein levels (P<0.05) in normotensive mice (Figure 2C) as well as enhanced ECM components, such as collagen type I, α-SMA, vimentin, TGF-β, and CTGF (P<0.05), but not OPN (Figure 2D and 2E). Moreover, CT-1–treated mice presented a significant increase in the inflammatory markers IL-1β and CCL-2 (P<0.05), but not in IL-6 protein expression (Figure 2E). The pharmacological inhibition of Gal-3 blocked all these changes induced by CT-1 (Figure 2D and 2F). Interestingly, CT-1–treated mice presented an increase in the phosphorylation of Stat-3 (P<0.05) and a tendency for ERK 1/2 phosphorylation, which were normalized by modified citrus pectin cotreatment (P<0.05; Figure 2F). Modified citrus pectin alone did not exert modifications in any of the parameters studied (data not shown).

Myocardial CT-1 and Gal-3 Are Increased and Associated With Myocardial Fibrosis in Hypertensive Rats With Diastolic Dysfunction

Dahl salt-sensitive hypertensive rats treated with a high-salt diet developed LV hypertrophy, as shown by increased LV mass corrected by body weight (P<0.001) and increased relative wall thickness (P<0.05), and diastolic dysfunction, shown by a decreased E/A ratio (P<0.05) and an increased isovolumetric relaxation time (P<0.05), with a preserved LV ejection fraction (Table S2). Additionally, they also showed signs and symptoms attributable to HF, such as respiratory distress, lethargy, and pulmonary edema. These animals presented global myocardial fibrosis (P<0.01) compared with control animals, characterized by an increase in both interstitial (P<0.05) and perivascular fibrosis (P<0.001; Figure 3A and 3B). When analyzing the composition of the arterial wall, the collagen content was higher both in arterioles (P<0.001) and arteries (P<0.01; Figure S3A).
Figure 3. The Dahl salt-sensitive rat. A, Left ventricular (LV) collagen volume fraction and interstitial and perivascular collagen volume fraction in control and in hypertensive rats with diastolic dysfunction and heart failure (DD). B, Representative images of interstitial and perivascular fibrosis in picrosirius red-stained sections from 1 control rat and 1 animal with DD (magnification ×10). C, CT-1 (cardiotrophin-1) myocardial expression in control and DD rats. D, Gal-3 (galectin-3) myocardial expression in control and DD rats. Data are shown as mean±SEM. *P<0.05; **P<0.01; ***P<0.001 vs control animals. E, Direct correlation between cardiac CT-1 protein expression and perivascular fibrosis in all animals (y=1.89x+2.04). F, Direct correlation between cardiac Gal-3 protein expression and perivascular fibrosis in all animals (y=4.65x+2.19). Values were normalized by 18S for mRNA and by β-actin for protein quantification, respectively.
The expression of CT-1 and Gal-3 was increased in the myocardium of HF rats both at mRNA (P<0.05 and P<0.01, respectively) and protein level (P<0.05; Figure 3C and 3D). Interestingly, myocardial CT-1 protein levels were correlated with myocardial Gal-3 mRNA levels (r=0.560; P<0.05) in all animals (Figure S3B). Myocardial CT-1 protein was correlated with myocardial fibrosis (r=0.438; P<0.05) and in particular with perivascular fibrosis (P<0.05; Figure 3E). However, myocardial Gal-3 protein was also correlated with perivascular fibrosis (P<0.001; Figure 3F) and tended to be correlated with global myocardial fibrosis (r=0.368; P=0.077). Of note, myocardial CT-1 protein and Gal-3 protein were associated with myocardial OPN mRNA expression (r=0.481, P<0.05 for CT-1 and r=0.571, P<0.01 for Gal-3).
CT-1 protein expression was correlated with the E/A ratio (r=−0.457; P<0.05). Additionally, Gal-3 was associated with the LV mass corrected by the body weight (r=0.570; P<0.01). Interestingly, increased macrophage infiltration (P<0.01; Figure S3C and S3D) and cardiac expression of the monocyte chemoattractant CCL-2 (P<0.01; Figure S3E) was found in the high-salt diet group. Macrophages were found both scattered in the interstitium and accumulated in the perivascular areas, specifically in the high-salt diet animals (Figure S3C).

Myocardial and Circulating CT-1 and Gal-3 Are Increased in HF Patients and Associated With Cardiovascular Death

In a small cohort of 24 patients with HF of hypertensive cause and proven histological myocardial fibrosis,9 both myocardial CT-1 (P<0.001) and Gal-3 (P<0.05) mRNA were increased as compared to control subjects (Figure 4A), and there was a direct correlation between both of them (P<0.01; Figure 4B).
Figure 4. Heart failure (HF) patients of hypertensive cause. A, Myocardial CT-1 (cardiotrophin-1) and Gal-3 (galectin-3) mRNA expression in control subjects and HF patients. Data are shown as mean±SEM. *P<0.05; ***P<0.001 vs control subjects. B, Direct correlation between cardiac CT-1 and Gal-3 mRNA in HF patients (y=0.5548x+0.25). C, Direct correlation between circulating CT-1 and Gal-3 in HF patients (y=0.11x+0.88). D, Unadjusted curves showing the cumulative incidence of cardiovascular death in patients stratified by CT-1 and Gal-3 cutoff values. FC indicates fold change.
In a larger cohort of 236 patients with HF of hypertensive cause, serum CT-1 and Gal-3 were increased as compared to control subjects (CT-1: 2966±1547 versus 1062±317 pg/mL, P<0.001; Gal-3: 18.51±17.35 versus 11.86±4.08 ng/mL, P<0.001), and there was a direct correlation between circulating levels of CT-1 and Gal-3 (P<0.05; Figure 4C). This association was independent of age, sex, systolic blood pressure, and body mass index but was affected by the estimated glomerular filtration rate (eGFR; P=0.100). Of note, CT-1 and Gal-3 have been shown to be involved in renal damage12,18and proposed as biomarkers of renal dysfunction.25,26 Both CT-1 and Gal-3 were associated with the eGFR (r=−0.259; P<0.01 and r=−0.177; P<0.05, respectively). Patients with an eGFR <60 mL/min (n=70) presented higher CT-1 (3443±228 versus 2717±96 pg/mL; P<0.05) and Gal-3 (22.18±0.91 versus 17.04±0.42 ng/mL; P<0.001) levels than patients with an eGFR ≥60 mL/min (n=154). Additionally, Gal-3 was also independently (including the eGFR) associated with the profibrotic marker OPN (r=0.395; P<0.05), the inflammation marker VCAM-1 (vascular cell adhesion molecule 1; r=0.272; P<0.001), high-sensitivity cardiac troponin T (r=0.395; P<0.001), and the left atrial volume index, a surrogate marker of diastolic dysfunction (r=0.183; P<0.01).
We evaluated the association of CT-1 and Gal-3 with cardiovascular death during a median follow-up of 5.44 years (range 0.24–8.0 years; Tables S3 and S4). Based on a receiver operating characteristics curves analysis (Figure S4 and Table S5), we established the cutoff values of 2630 and 19 ng/mL for CT-1 and Gal-3 levels, respectively (Table S5). Subsequently, we stratified HF patients in 3 groups: Patients with both parameters below the cutoff values (n=72); patients with 1 parameter above the cutoff values (n=118); and patients with both parameters above the cutoff values (n=46; Table S6 and Table 1). Of note, NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity cardiac troponin T, and OPN levels increased progressively along these 3 groups (Table S6). Longitudinal analysis showed that HF patients with either CT-1 or Gal-3 above the cutoff values (P=0.027; Figure 4D), and especially patients with both parameters above the cutoff values (P<0.001; Figure 4D), had a higher risk of cardiovascular death than HF patients with normal values. Finally, the multivariable competing risk analyses showed that patients with both parameters above the cutoff values had at least a 2.6-fold higher risk of cardiovascular death than patients with both parameters below these values in 3 different models including relevant clinical and echocardiographic variables (ie, age, sex, cardiac hypertrophy, eGFR, dyslipidemia, New York Heart Association functional class, NT-proBNP, LV ejection fraction, and E/e′; Table 2).
Table 1. Echocardiographic Parameters in Heart Patients Stratified According to CT-1 and Gal-3 Levels
ParameterCT-1–Based and Gal-3–Based GroupsP for Trend
CT-1 <2.63 ng/mL and Gal-3 <19 ng/mL (n=72)CT-1 ≥2.63 ng/mL or Gal-3 ≥19 ng/mL (n=118)CT-1 ≥2.63 ng/mL and Gal-3 ≥19 ng/mL (n=46)
LVMI, g/m2143±52.0151±63.7161±58.6<0.001
RWT0.44±0.110.43±0.130.46±0.13NS
LVEDD, mm49.2±8.051.2±9.352.1±9.20.08
LVVI, mL/m264.0±22.870.9±30.272.9±29.40.08
LVEF, %58.0±15.555.7±17.053.7±14.0NS
E, cm/s87.5±20.690.0±28.588.3±32.2NS
E:A ratio0.9±0.30.9±0.40.9±0.4NS
IVR, ms107±20.2109±27.9107±29.7NS
DT, ms216±54.9205±56.2213±59.9NS
e′, cm/s8.2±2.88.3±2.77.3±2.3NS
E/e′ ratio11.1±3.911.7±4.612.5±5.50.09
LAVI, mL/m238.0±12.643.3±15.942.8±13.60.05
Values are expressed as mean±SD. A indicates maximum late transmitral flow velocity in diastole; CT-1, cardiotrophin-1; DT, deceleration time; e′, maximum early mitral annulus velocity in diastole; E, maximum early transmitral flow velocity in diastole; Gal-3, galectin-3; IVRT, isovolumetric relaxation time; LAVI, left atrial volume index; LVEDD, LV end-diastolic diameter; LVEF, LV ejection fraction; LVMI, left ventricular mass index; LVVI, LV end-systolic volume index; NS, nonsignificant; and RWT, relative wall thickness.
Table 2. Multivariate Cox Regression Analysis for Prediction of Cardiovascular Death in Patients Stratified According to CT-1 and Gal-3 Values
ParameterHazard Ratio95% CIP Value
Model 1 (age and sex)
 CT-1 <2630 pg/mL and Gal-3 <19 ng/mL1.00 (Ref)  
 CT-1 ≥2630 pg/mL or Gal-3 ≥19 ng/mL2.011.03–6.81<0.05
 CT-1 ≥2630 pg/mL and Gal-3 ≥19 ng/mL3.321.98–14.1<0.01
Model 2 (NYHA, LVMI, eGFR <60 mL/min, dyslipidemia)
 CT-1 <2630 pg/mL and Gal-3 <19 ng/mL1.00 (Ref)  
 CT-1 ≥2630 pg/mL or Gal-3 ≥19 ng/mL1.770.90–8.26>0.05
 CT-1 ≥2630 pg/mL and Gal-3 ≥19 ng/mL2.601.48–15.8<0.01
Model 3 (E/e′, NT-proBNP, LVEF)
 CT-1 <2630 pg/mL and Gal-3 <19 ng/mL1.00 (Ref)  
 CT-1 ≥2630 pg/mL or Gal-3 ≥19 ng/mL2.380.84–6.73>0.05
 CT-1 ≥2630 pg/mL and Gal-3 ≥19 ng/mL5.141.76–15.0<0.01
CT-1 indicates cardiotrophin-1; E/e’, peak early velocity of the transmitral flow (E) divided by the peak early diastolic velocity of the mitral annulus displacement (e’); eGFR, estimated glomerular filtration rate; Gal-3, galectin-3; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; NYHA, New York Heart Association; and NT-proBNP, N-terminal pro-B-type natriuretic peptide.

Discussion

The purpose of this study was to investigate whether Gal-3 is involved in the ability of CT-1 to induce myocardial inflammation and fibrosis. Through a proteomic approach, we have described for the first time that CT-1 increased the expression of Gal-3 in HCFs. This effect was confirmed in vivo in rats and mice treated with CT-1. Gal-3 genetic disruption in cardiac cells or pharmacological Gal-3 inhibition in CT-1 treated mice prevented the profibrotic and proinflammatory effects of CT-1. Thus, Gal-3 emerges as a downstream mediator of CT-1 in myocardial inflammation and fibrosis. Moreover, CT-1 and Gal-3 levels were increased in an animal model of hypertensive HF with diastolic dysfunction and in myocardial biopsies of hypertensive patients with chronic HF. Interestingly, myocardial and plasma CT-1 levels were directly correlated with myocardial and plasma Gal-3 levels in HF patients, respectively. In addition, patients with high CT-1 and high Gal-3 levels presented a higher risk of cardiovascular death, supporting the relevance of this axis in the progression of HF.
Both CT-19 and Gal-319 have been found to be increased in the myocardium of HF patients and proposed to play a role in the pathological myocardial remodeling that underlies HF development and progression. Previous studies have demonstrated the profibrotic effects of CT-1 in cardiac fibroblasts,9 as well as in rats vascular smooth muscle cells.27 In accordance with these data, we have observed that CT-1 enhanced ECM proteins expression in HCFs. In addition, Gal-3 is expressed in several cell types in the myocardium and colocalized with fibroblasts, inflammatory, and endothelial markers. Moreover, CT-1–treated mice developed myocardial fibrosis, and in hypertensive HF rats with diastolic dysfunction, there was an association between increased CT-1 and myocardial fibrosis, in particular with perivascular fibrosis. In line with these observations, previous studies from our group demonstrated in rats that chronic CT-1 exposure induced myocardial fibrosis.12 Similarly, in HF patients myocardial CT-1 correlated with cardiac collagen type I and III expression.9
In the present study, we show for the first time that the deleterious effects induced by CT-1 in vitro and in vivo were accompanied by an increase in cardiac Gal-3 protein levels and that cardiac CT-1 and Gal-3 were associated in HF patients and rats. Moreover, CT-1 increased Gal-3 levels through ERK 1/2 and Stat-3 pathways, 2 mechanisms involved in the development of cardiac fibrosis and hypertrophy.28 Interestingly, LV hypertrophy and myocardial fibrosis present in CT-1–treated mice were prevented by the treatment with a Gal-3 pharmacological inhibitor. We and others have demonstrated the proinflammatory and profibrotic role of Gal-3 at the cardiac level.21,29 In CT-1–treated rats, Gal-3 was mainly located at the perivascular areas and associated with perivascular fibrosis. Interestingly, cardiac microvasculature plays a major role in facilitating myocardial inflammation and fibrosis in HF with preserved ejection fraction.3 In this context, there was an increase of macrophages (in the interstitium and perivascular areas) and inflammation markers in CT-1 treated rats and in our HF rat model, supporting the involvement of inflammation in this process.
Several pathways contribute to the development of myocardial fibrosis in HF patients. The renin-angiotensin-aldosterone system plays an important role in the development and progression of hypertension-related HF. Angiotensin II and aldosterone regulate both the expression of CT-122,30 and Gal-3.23,29 Of note, a local cardiac increase of both angiotensin II and aldosterone has been found in the hypertensive Dahl salt-sensitive rat,31 suggesting that the cardiac increase in CT-1 and Gal-3 may be due, at least partly, to the activation of the renin-angiotensin-aldosterone system.
Of note, the association of cardiac Gal-3 with myocardial fibrosis in human HF seems to be dependent on the pathogenesis of HF. Whereas a direct association between cardiac Gal-3 and myocardial fibrosis was found in patients with dilated cardiomyopathy,32 there was no correlation in elderly hypertensive HF patients.19 Moreover, in patients with inflammatory cardiomyopathy, Gal-3 was more strongly associated with immune cells count.32 This may be related to the fact that macrophages are one of the major sources of Gal-3. Accordingly, in a rat HF model, there was an increase in cardiac Gal-3 colocalized with macrophages in areas of myocardial tissue damage.33 Therefore, these findings highlight the pleiotropic biological functions of Gal-3 and the necessity to further study the myocardial effects of Gal-3 in the clinical setting.
From a clinical perspective, we have found that elevation of both plasma CT-1 and Gal-3 was associated with increased cardiovascular mortality. Elevated Gal-3 levels have been found to be associated with a higher risk of cardiovascular death in acute decompensated HF patients as shown in the PRIDE (Pro-BNP Investigation of Dyspnea in the Emergency Department)34 and COACH (Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure)35 clinical trials. In chronic HF, the ability of Gal-3 for predicting mortality has been reported in patients with HF with reduced ejection fraction20 and with HF with preserved ejection fraction.36 Regarding CT-1, it has been proposed as a biomarker of cardiac hypertrophy,10,11 and shown to be associated with HF,11 but an association with cardiovascular death has been only reported in patients with HF with reduced ejection fraction, mostly due ischemic and dilated cardiomyopathy.37 Therefore, our current findings corroborate and expand these previous data to patients with either HF with preserved ejection fraction or HF with reduced ejection fraction of hypertensive cause. Importantly, for the first time, we show that the combination of high CT-1 and high Gal-3 identifies a subgroup of patients with chronic HF of hypertensive cause with a higher risk of cardiovascular death, highlighting the pathophysiological relevance of the activation of the CT-1/Gal-3 axis.
The current study presents a number of limitations to be considered when interpreting the data. First, about the Dahl salt-sensitive rat, this model involves the activation of several hemodynamic and humoral mechanisms both systemically a locally; therefore, we cannot exclude that other factors (eg, hypertension, angiotensin II, aldosterone) may contribute to myocardial fibrosis through additional alternative mechanisms. Second, about the clinical studies, a relatively small number of patients were included, mainly for the molecular studies of cardiac mRNA. Third, an association was found between CT-1, Gal-3, and renal function. Chronic kidney disease plays a major role in the development of HF; therefore, its influence in the CT-1/Gal-3 axis merits to be specifically studied. Fourth, only HF patients of hypertensive cause were evaluated and, therefore, the results obtained may not be extrapolated to other causes. Overall the findings of the clinical study are largely observational, and the potential prognostic usefulness of this combination needs to be further evaluated in larger multicenter cohorts with HF of different causes.

Perspectives

In conclusion, in experimental models, cardiac CT-1 and Gal-3 were associated with myocardial fibrosis, predominantly perivascular fibrosis. CT-1 upregulated Gal-3 expression, and Gal-3 blockade prevented the proinflammatory and profibrotic effects of CT-1 both in vitro and in vivo. In HF patients, elevated CT-1 and Gal-3 were associated with a higher risk of cardiovascular mortality. Altogether, these data suggest that CT-1 and Gal-3 are involved in the progression of HF, with Gal-3 mediating the proinflammatory and profibrotic actions of CT-1. Further studies are necessary to elucidate the impact of this axis in HF patients of different causes and to evaluate the usefulness of therapeutic strategies aimed at the inhibition of this system.

Acknowledgments

We thank María González, Laura Martínez, and Sonia Martínez for their technical support.

Novelty and Significance

What Is New?

•
CT-1 (cardiotrophin-1) regulates Gal-3 (galectin-3) expression.
•
Gal-3 inhibition prevents the proinflammatory-profibrotic actions of CT-1.
•
CT-1 and Gal-3 are associated with perivascular fibrosis in animal models.

What Is Relevant?

•
The CT-1/Gal-3 axis is involved in the inflammatory-fibrotic response in the myocardium.
•
Elevated CT-1 and Gal-3 are associated with increased risk of cardiovascular death in HF patients of hypertensive cause.

Summary

In experimental models, cardiac CT-1 and Gal-3 were associated with myocardial fibrosis, predominantly perivascular fibrosis. CT-1 upregulated Gal-3 expression and, Gal-3 blockade prevented the proinflammatory-profibrotic effects of CT-1 both in vitro and in vivo. In heart failure patients, elevated CT-1 and Gal-3 correlated between them and were associated with higher cardiovascular mortality.

Supplemental Material

File (hyp_hype201811874_supp1.pdf)
File (hyp_hype201811874_supp2.pdf)

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Information & Authors

Information

Published In

Go to Hypertension
Go to Hypertension
Hypertension
Volume 73 • Number 3 • March 2019
Pages: 602 - 611
PubMed: 30612490

Copyright

© 2019 American Heart Association, Inc.

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History

Received: 25 July 2018
Revision received: 10 August 2018
Accepted: 13 December 2018
Published online: 7 January 2019
Published in print: March 2019

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Keywords

  1. cardiotrophin-1
  2. fibroblasts
  3. galectin-3
  4. heart failure
  5. inflammation

Subjects

  1. Basic Science Research
  2. Biomarkers
  3. Fibrosis
  4. Translational Studies

Authors

Affiliations

Ernesto Martínez-Martínez
From the Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona. Spain (E.M.-M., J.I., A.F.-C., N.L.-A.)
INSERM UMRS 1138 Team 1, Centre de Recherche des Cordeliers, University Pierre and Marie Curie, Paris, France (E.M.M., M.B., F.J.)
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Cristina Brugnolaro
Program of Cardiovascular Diseases, CIMA University of Navarra and IdiSNA, Pamplona. Spain (C.B., S.R., B.L., M.U.M., J.D., A.G.)
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Jaime Ibarrola
From the Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona. Spain (E.M.-M., J.I., A.F.-C., N.L.-A.)
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Susana Ravassa
Program of Cardiovascular Diseases, CIMA University of Navarra and IdiSNA, Pamplona. Spain (C.B., S.R., B.L., M.U.M., J.D., A.G.)
CIBERCV, Carlos III Institute of Health, Madrid. Spain (S.R., B.L., M.U.M., J.D., A.G.)
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Mathieu Buonafine
INSERM UMRS 1138 Team 1, Centre de Recherche des Cordeliers, University Pierre and Marie Curie, Paris, France (E.M.M., M.B., F.J.)
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Begoña López
Program of Cardiovascular Diseases, CIMA University of Navarra and IdiSNA, Pamplona. Spain (C.B., S.R., B.L., M.U.M., J.D., A.G.)
CIBERCV, Carlos III Institute of Health, Madrid. Spain (S.R., B.L., M.U.M., J.D., A.G.)
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Amaya Fernández-Celis
From the Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona. Spain (E.M.-M., J.I., A.F.-C., N.L.-A.)
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Ramón Querejeta
Department of Cardiology, Donostia University Hospital, Biodonostia, Basque Country University, San Sebastián, Spain (R.Q.)
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Enrique Santamaria
Proteored-ISCIII, Proteomics Unit, Navarrabiomed, Departamento de Salud, UPNA, IdiSNA, Pamplona, Spain (E.S., J.F.-I.)
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Joaquín Fernández-Irigoyen
Proteored-ISCIII, Proteomics Unit, Navarrabiomed, Departamento de Salud, UPNA, IdiSNA, Pamplona, Spain (E.S., J.F.-I.)
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Gregorio Rábago
Department of Cardiology and Cardiac Surgery (G.R., J.D.), Clinic Universtity of Navarra, Pamplona. Spain
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María U Moreno
Program of Cardiovascular Diseases, CIMA University of Navarra and IdiSNA, Pamplona. Spain (C.B., S.R., B.L., M.U.M., J.D., A.G.)
CIBERCV, Carlos III Institute of Health, Madrid. Spain (S.R., B.L., M.U.M., J.D., A.G.)
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Frédéric Jaisser
INSERM UMRS 1138 Team 1, Centre de Recherche des Cordeliers, University Pierre and Marie Curie, Paris, France (E.M.M., M.B., F.J.)
INSERM, Centre d’Investigations Cliniques-Plurithématique 1433, UMR 1116 Université de Lorraine, CHRU de Nancy, France (F.J., N.L.-A.).
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Javier Díez
Program of Cardiovascular Diseases, CIMA University of Navarra and IdiSNA, Pamplona. Spain (C.B., S.R., B.L., M.U.M., J.D., A.G.)
CIBERCV, Carlos III Institute of Health, Madrid. Spain (S.R., B.L., M.U.M., J.D., A.G.)
Department of Cardiology and Cardiac Surgery (G.R., J.D.), Clinic Universtity of Navarra, Pamplona. Spain
Department of Nephrology (J.D.), Clinic Universtity of Navarra, Pamplona. Spain
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Arantxa González* [email protected]
Program of Cardiovascular Diseases, CIMA University of Navarra and IdiSNA, Pamplona. Spain (C.B., S.R., B.L., M.U.M., J.D., A.G.)
CIBERCV, Carlos III Institute of Health, Madrid. Spain (S.R., B.L., M.U.M., J.D., A.G.)
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Natalia López-Andrés* [email protected]
From the Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona. Spain (E.M.-M., J.I., A.F.-C., N.L.-A.)
INSERM, Centre d’Investigations Cliniques-Plurithématique 1433, UMR 1116 Université de Lorraine, CHRU de Nancy, France (F.J., N.L.-A.).
View all articles by this author

Notes

*
These authors contributed equally to this study.
The online-only Data Supplement is available with this article at Supplemental Material.
Correspondence to Arantxa González, Program of Cardiovascular Diseases, CIMA University of Navarra and IdiSNA, Avda/ Pío XII 55, 31008 Pamplona, Spain, Email [email protected]
Natalia López-Andrés, Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Irunlarrea 3, 31008 Pamplona, Spain, Email [email protected]

Disclosures

None.

Sources of Funding

This project was funded by the Ministry of Economy and Competitiveness from Spain (Instituto de Salud Carlos III: CIBERCV (Centro de Investigación en Red en Enfermedades Cardiovasculares) CB16/11/00483, PI15/01909, and PI15/02160 co-financed by FEDER [Fondo Europeo de Desarrollo Regional] funds), the European Commission FP7 Programme (HOMAGE project 2012–305507 and FIBROTARGETS project 2013–602904), the ERA-CVD (European Research Area Network on Cardiovascular Diseases) Joint Transnational Call 2016 LYMIT-DIS (AC16/00020), the FP7-funded COST ADMIRE network (BM1301), ANR MRFOCUS (ANR-15-CE14-0032-02), the Fight-HF Avenir investment program (ANR-15-RHUS-0004), grants from the Institut National de la Santé et de la Recherche Médicale, the Centre de Recherche Industrielle et Technique. N. López-Andrés was supported by a Miguel Servet contract CP13/00221 from the Instituto de Salud Carlos III-FEDER. E. Martínez-Martínez was supported by a contract from CAM (atracción de talento). The Proteomics Unit of Navarrabiomed is a member of Proteored, PRB3-ISCIII (Instituto de Salud Carlos III), and is supported by grant PT17/0019/009, of the PE I+D+I 2018 to 2020 funded by ISCIII and FEDER.

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CT-1 (Cardiotrophin-1)-Gal-3 (Galectin-3) Axis in Cardiac Fibrosis and Inflammation
Hypertension
  • Vol. 73
  • No. 3

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