Unraveling the role of galectin-3 in cardiac pathology and physiology

Galectin-3 (Gal-3) is a carbohydrate-binding protein with multiple functions. Gal-3 regulates cell growth, proliferation, and apoptosis by orchestrating cell-cell and cell-matrix interactions. It is implicated in the development and progression of cardiovascular disease, and its expression is increased in patients with heart failure. In atherosclerosis, Gal-3 promotes monocyte recruitment to the arterial wall boosting inflammation and atheroma. In acute myocardial infarction (AMI), the expression of Gal-3 increases in infarcted and remote zones from the beginning of AMI, and plays a critical role in macrophage infiltration, differentiation to M1 phenotype, inflammation and interstitial fibrosis through collagen synthesis. Genetic deficiency of Gal-3 delays wound healing, impairs cardiac remodeling and function after AMI. On the contrary, Gal-3 deficiency shows opposite results with improved remodeling and function in other cardiomyopathies and in hypertension. Pharmacologic inhibition with non-selective inhibitors is also protective in cardiac disease. Finally, we recently showed that Gal-3 participates in normal aging. However, genetic absence of Gal-3 in aged mice exacerbates pathological hypertrophy and increases fibrosis, as opposed to reduced fibrosis shown in cardiac disease. Despite some gaps in understanding its precise mechanisms of action, Gal-3 represents a potential therapeutic target for the treatment of cardiovascular diseases and the management of cardiac aging. In this review, we summarize the current knowledge regarding the role of Gal-3 in the pathophysiology of heart failure, atherosclerosis, hypertension, myocarditis, and ischemic heart disease. Furthermore, we describe the physiological role of Gal-3 in cardiac aging

Enhanced Interleukin-1 Activity Contributes to Exercise Intolerance in Patients with Systolic Heart Failure

Contains fulltext : 107753.pdf (publisher's version ) (Open Access)BACKGROUND: Heart failure (HF) is a complex clinical syndrome characterized by impaired cardiac function and poor exercise tolerance. Enhanced inflammation is associated with worsening outcomes in HF patients and may play a direct role in disease progression. Interleukin-1beta (IL-1beta) is a pro-inflammatory cytokine that becomes chronically elevated in HF and exerts putative negative inotropic effects. METHODS AND RESULTS: We developed a model of IL-1beta-induced left ventricular (LV) dysfunction in healthy mice that exhibited a 32% reduction in LV fractional shortening (P<0.001) and a 76% reduction in isoproterenol response (P<0.01) at 4 hours following a single dose of IL-1beta 3 mcg/kg. This phenotype was reproducible in mice injected with plasma from HF patients and fully preventable by pretreatment with IL-1 receptor antagonist (anakinra). This led to the design and conduct of a pilot clinical to test the effect of anakinra on cardiopulmonary exercise performance in patients with HF and evidence of elevated inflammatory signaling (n = 7). The median peak oxygen consumption (VO(2)) improved from 12.3 [10.0, 15.2] to 15.1 [13.7, 19.3] mL . kg(-1) . min(-1) (P = 0.016 vs. baseline) and median ventilator efficiency (V(E)/VCO(2) slope) improved from 28.1 [22.8, 31.7] to 24.9 [22.9, 28.3] (P = 0.031 vs. baseline). CONCLUSIONS: These findings suggest that IL-1beta activity contributes to poor exercise tolerance in patients with systolic HF and identifies IL-1beta blockade as a novel strategy for pharmacologic intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT01300650

Alterations in the Interleukin-1/Interleukin-1 Receptor Antagonist Balance Modulate Cardiac Remodeling following Myocardial Infarction in the Mouse

Background Healing after acute myocardial infarction (AMI) is characterized by an intense inflammatory response and increased Interleukin-1 (IL-1) tissue activity. Genetically engineered mice lacking the IL-1 receptor (IL-1R1-/-, not responsive to IL-1) or the IL-1 receptor antagonist (IL-1Ra, enhanced response to IL-1) have an altered IL-1/IL-1Ra balance that we hypothesize modulates infarct healing and cardiac remodeling after AMI. Methods IL-1R1-/- and IL-1Ra-/- male mice and their correspondent wild-types (WT) were subjected to permanent coronary artery ligation or sham surgery. Infarct size (trichrome scar size), apoptotic cell death (TUNEL) and left ventricular (LV) dimensions and function (echocardiography) were measured prior to and 7 days after surgery. Results When compared with the corresponding WT, IL-1R1-/- mice had significantly smaller infarcts (−25%), less cardiomyocyte apoptosis (−50%), and reduced LV enlargement (LV end-diastolic diameter increase [LVEDD], −20%) and dysfunction (LV ejection fraction [LVEF] decrease, −50%), whereas IL-1Ra-/- mice had significantly larger infarcts (+75%), more apoptosis (5-fold increase), and more severe LV enlargement (LVEDD increase,+30%) and dysfunction (LVEF decrease, +70%)(all P values \u3c0.05). Conclusions An imbalance in IL-1/IL-1Ra signaling at the IL-1R1 level modulates the severity of cardiac remodeling after AMI in the mouse, with reduced IL-1R1 signaling providing protection and unopposed IL-1R1 signaling providing harm

Galectin-1 as an Emerging Mediator of Cardiovascular Inflammation: Mechanisms and Therapeutic Opportunities

Galectin-1 (Gal-1), an evolutionarily conserved β-galactoside-binding lectin, controls immune cell homeostasis and tempers acute and chronic inflammation by blunting proinflammatory cytokine synthesis, engaging T-cell apoptotic programs, promoting expansion of T regulatory (Treg) cells, and deactivating antigen-presenting cells. In addition, this lectin promotes angiogenesis by co-opting the vascular endothelial growth factor receptor (VEGFR) 2 signaling pathway. Since a coordinated network of immunomodulatory and proangiogenic mediators controls cardiac homeostasis, this lectin has been proposed to play a key hierarchical role in cardiac pathophysiology via glycan-dependent regulation of inflammatory responses. Here, we discuss the emerging roles of Gal-1 in cardiovascular diseases including acute myocardial infarction, heart failure, Chagas cardiomyopathy, pulmonary hypertension, and ischemic stroke, highlighting underlying anti-inflammatory mechanisms and therapeutic opportunities. Whereas Gal-1 administration emerges as a potential novel treatment option in acute myocardial infarction and ischemic stroke, Gal-1 blockade may contribute to attenuate pulmonary arterial hypertension

Inflammatory markers in STelevation acute myocardial infarction

After acute myocardial infarction, ventricular remodeling is characterized by changes at the molecular, structural, geometrical and functional level that determine progression to heart failure. Inflammation plays a key role in wound healing and scar formation, affecting ventricular remodeling. Several, rather different, components of the inflammatory response were studied as biomarkers in ST-elevation acute myocardial infarction. Widely available and inexpensive tests, such as leukocyte count at admission, as well as more sophisticated immunoassays provide powerful predictors of adverse outcome in patients with ST-elevation acute myocardial infarction. We review the value of inflammatory markers in ST-elevation acute myocardial infarction and their association with ventricular remodeling, heart failure and sudden death. In conclusion, the use of these biomarkers may identify subjects at greater risk of adverse events and perhaps provide an insight into the mechanisms of disease progression