Objective-Aldosterone (Aldo) is involved in arterial stiffness and heart failure, but the mechanisms have remained unclear. Galectin-3 (Gal-3), a β-galactoside-binding lectin, plays an important role in inflammation, fibrosis, and heart failure. We investigated here whether Gal-3 is involved in Aldo-induced vascular fibrosis. Methods and Results-In rat vascular smooth muscle cells Gal-3 overexpression enhanced specifically collagen type I synthesis. Moreover Gal-3 inhibition by modified citrus pectin or small interfering RNA blocked Aldo-induced collagen type I synthesis. Rats were treated with Aldo-salt combined with spironolactone or modified citrus pectin for 3 weeks. Hypertensive Aldo-treated rats presented vascular hypertrophy, inflammation, fibrosis, and increased aortic Gal-3 expression. Spironolactone or modified citrus pectin treatment reversed all the above effects. Wild-type and Gal-3 knockout mice were treated with Aldo for 6 hours or 3 weeks. Aldo increased aortic Gal-3 expression, inflammation, and collagen type I in wild-type mice at both the short-and the long-term, whereas no changes occurred in Gal-3 knock-out mice. Conclusion-Our data indicate that

AimsCirculating biomarkers of collagen turnover reflect extracellular cardiac matrix (ECCM) remodelling. The extent to which the success of cardiac resynchronization therapy (CRT) is influenced by the degree of cardiac fibrosis and whether CRT can influence matrix remodelling has yet to be studied. Our aim was to determine, in patients with heart failure (HF) and cardiac dyssynchrony, whether ECCM biomarkers are influenced by CRT and can predict cardiovascular outcomes and response to CRT. Methods and resultsSerum levels of ECCM biomarkers , N-terminal propeptides of type I and III procollagens (PINP and PIIINP), type I collagen telopeptide (ICTP), and matrix metalloproteinase 1 (MMP-1)] were measured in 260 patients, in a substudy of CARE-HF, a randomized controlled trial which evaluated the effects of CRT in patients with left ventricular systolic dysfunction and cardiac dyssynchrony. ECCM biomarkers did not change throughout the 18-month follow-up period. In age-and gender-adjusted analyses, Gal-3 and PIIINP were associated with death or HF hospitalization. In a further multivariate model, Gal-3 .30 ng/mL was associated [OR (95% CI): 2.98 (1.43-6.22), P ¼ 0.004] with death or HF hospitalization, along with left ventricular end-systolic volume .200 mL [3.42 (OR: 1.65 -7.10), P ¼ 0.001]. The outcome death or left ventricular ejection fraction (LVEF) ≤35% was associated with MMP-1 [≤3 ng/mL: 3.04 (1.37-6.71), P ¼ 0.006]. No significant interaction was observed between the tested biomarkers and the treatment group. ConclusionsIncreased Gal-3 and PIIINP, and low MMP-1 are associated with adverse long-term cardiovascular outcomes but did not predict response to CRT. CRT did not favourably affect serum concentrations of ECCM markers.--

Fibrosis is a pivotal player in heart failure development and progression. Measurements of (markers of) fibrosis in tissue and blood may help to diagnose and risk stratify patients with heart failure, and its treatment may be effective in preventing heart failure and its progression. A lack of pathophysiological insights and uniform definitions has hampered the research in fibrosis and heart failure. The Translational Research Committee of the Heart Failure Association discussed several aspects of fibrosis in their workshop. Early insidious perturbations such as subclinical hypertension or inflammation may trigger first fibrotic events, while more dramatic triggers such as myocardial infarction and myocarditis give rise to full blown scar formation and ongoing fibrosis in diseased hearts. Aging itself is also associated with a cardiac phenotype that includes fibrosis. Fibrosis is an extremely heterogeneous phenomenon, as several stages of the fibrotic process exist, each with different fibrosis subtypes and a different composition of various cells and proteins — resulting in a very complex pathophysiology. As a result, detection of fibrosis, e.g. using current cardiac imaging modalities or plasma biomarkers, will detect only specific subforms of fibrosis, but cannot capture all aspects of the complex fibrotic process. Furthermore, several anti‐fibrotic therapies are under investigation, but such therapies generally target aspecific aspects of the fibrotic process and suffer from a lack of precision. This review discusses the mechanisms and the caveats and proposes a roadmap for future research.

In experimental hyperaldosteronism, the increase in Gal-3 expression was associated with cardiac and renal fibrosis and dysfunction but was prevented by pharmacological inhibition (modified citrus pectin) or genetic disruption of Gal-3. These data suggest a key role for Gal-3 in cardiorenal remodeling and dysfunction induced by aldosterone. Gal-3 could be used as a new biotarget for specific pharmacological interventions.

Hypertensive cardiac remodeling is accompanied by molecular inflammation and fibrosis, 2 mechanisms that finally affect cardiac function. At cardiac level, aldosterone promotes inflammation and fibrosis, although the precise mechanisms are still unclear. Galectin-3 (Gal-3), a β-galactoside–binding lectin, is associated with inflammation and fibrosis in the cardiovascular system. We herein investigated whether Gal-3 inhibition could block aldosterone-induced cardiac inflammation and fibrosis and its potential role in cardiac damage associated with hypertension. Aldosterone-salt–treated rats presented hypertension, cardiac inflammation, and fibrosis that were prevented by the pharmacological inhibition of Gal-3 with modified citrus pectin. Cardiac inflammation and fibrosis presented in spontaneously hypertensive rats were prevented by modified citrus pectin treatment, whereas Gal-3 blockade did not modify blood pressure levels. In the absence of blood pressure modifications, Gal-3 knockout mice were resistant to aldosterone-induced cardiac inflammation. In human cardiac fibroblasts, aldosterone increased Gal-3 expression via its mineralocorticoid receptor. Gal-3 and aldosterone enhanced proinflammatory and profibrotic markers, as well as metalloproteinase activities in human cardiac fibroblasts, effects that were not observed in Gal-3–silenced cells treated with aldosterone. In experimental hyperaldosteronism, the increase in Gal-3 expression was associated with cardiac inflammation and fibrosis, alterations that were prevented by Gal-3 blockade independently of blood pressure levels. These data suggest that Gal-3 could be a new molecular mechanism linking cardiac inflammation and fibrosis in situations with high-aldosterone levels, such as hypertension.

The data suggest that leptin locally produced in the heart could participate in the fibrosis observed in HFD by affecting collagen turnover. Collagen synthesis induced by leptin seems to be mediated by the production of galectin-3, TGF-β and CTGF through oxidative stress increased by activation of mTOR pathway.

Myocardial fibrosis is the result of excessive fibrillar collagen synthesis and deposition without reciprocally balanced degradation. It causes cardiac dysfunction, arrhythmias, and ischaemia, and thereby determines the clinical course and outcome of cardiac patients even when adequately treated. Therefore, further research is needed to identify and better understand the factors that trigger and maintain the myocardial fibrotic response against different injuries in a variety of cardiac diseases. Here, we will focus on the following major areas of research: molecules that stimulate the differentiation of fibroblasts into myofibroblasts and subsequently alter collagen turnover (e.g. cardiotrophin-1, galectin-3, NADPH oxidases, and neutrophil gelatinase-associated lipocalin), microRNA-induced alterations of collagen gene expression, and matricellular protein-and lysyl oxidase-mediated alterations of collagen cross-linking and deposition.

A ldosterone via the activation of the mineralocorticoid receptor (MR) is a main actor of renal sodium reabsorption and water homeostasis. Extra-renal effects of the mineralocorticoid pathway have now been characterized, especially in the cardiovascular system, opening on new dimensions of the aldosterone/MR pathway in physiology, pathophysiology, and diseases. In the cardiovascular system, mineralocorticoid signaling has been shown to play an important role in the progression of cardiovascular diseases (CVDs). Previous reports using transgenic mouse models or pharmacological approaches demonstrated adverse effects of aldosterone on cardiac remodeling and fibrosis, inflammation, and hypertension.1 These features are prevented by the pharmacological blockade of the MR. In humans, several clinical studies showed the beneficial effects of MR antagonism in addition to standard care, to reduce mortality and morbidity in patients with severe 2 or mild heart failure (HF) 3 or after acute myocardial infarction. 4 Understanding the molecular mechanisms of mineralocorticoid activation pathway in cardiovascular pathophysiology remains incomplete. Indeed, a better knowledge of the underlying mechanisms may highlight novel mediators of the MR signaling cascade. These newly identified intermediates could be good candidates as biotargets for novel pharmacological approaches, especially in diseases where the aldosterone/MR pathway is involved. Moreover, these biotargets may as well be considered as potent biomarkers of MR activation, Abstract-Activation of the mineralocorticoid receptor has been shown to be deleterious in cardiovascular diseases (CVDs).We have recently shown that lipocalin 2 (Lcn2), or neutrophil gelatinase-associated lipocalin (NGAL), is a primary target of aldosterone/mineralocorticoid receptor in the cardiovascular system. Lcn2 is a circulating protein, which binds matrix metalloproteinase 9 and modulates its stability. We hypothesized that Lcn2 could be a mediator of aldosterone/ mineralocorticoid receptor profibrotic effects in the cardiovascular system. Correlations between aldosterone and profibrotic markers, such as procollagen type I N-terminal peptide, were investigated in healthy subjects and subjects with abdominal obesity. The implication of Lcn2 in the mineralocorticoid pathway was studied using Lcn2 knockout mice subjected to a nephrectomy/aldosterone/salt (NAS) challenge for 4 weeks. In human subjects, NGAL/matrix metalloproteinase 9 was positively correlated with plasma aldosterone and fibrosis biomarkers. In mice, loss of Lcn2 prevented the NAS-induced increase of plasma procollagen type I N-terminal peptide, as well as the increase of collagen fibers deposition and collagen I expression in the coronary vessels and the aorta. The lack of Lcn2 also blunted the NAS-induced increase in systolic blood pressure. Ex vivo, treatment of human fibroblasts with recombinant Lcn2 induced the expression of collagen I and the profibrotic galectin-3 and cardiotrophin-1 molecules. allowing a better selectio...