Mechanisms responsible for increased circulating levels of galectin-3 in cardiomyopathy and heart failure

Abstract

Galectin-3 is a biomarker of heart disease. However, it remains unknown whether increase in galectin-3 levels is dependent on aetiology or disease-associated conditions and whether diseased heart releases galectin-3 into the circulation. We explored these questions in mouse models of heart disease and in patients with cardiomyopathy. All mouse models (dilated cardiomyopathy, DCM; fibrotic cardiomyopathy, ischemia-reperfusion, I/R; treatment with β-adrenergic agonist isoproterenol) showed multi-fold increases in cardiac galectin-3 expression and preserved renal function. In mice with fibrotic cardiomyopathy, I/R or isoproterenol treatment, plasma galectin-3 levels and density of cardiac inflammatory cells were elevated. These models also exhibited parallel changes in cardiac and plasma galectin-3 levels and presence of trans-cardiac galectin-3 gradient, indicating cardiac release of galectin-3. DCM mice showed no change in circulating galectin-3 levels nor trans-cardiac galectin-3 gradient or myocardial inflammatory infiltration despite a 50-fold increase in cardiac galectin-3 content. In patients with hypertrophic cardiomyopathy or DCM, plasma galectin-3 increased only in those with renal dysfunction and a trans-cardiac galectin-3 gradient was not present. Collectively, this study documents the aetiology-dependency and diverse mechanisms of increment in circulating galectin-3 levels. Our findings highlight cardiac inflammation and enhanced β-adrenoceptor activation in mediating elevated galectin-3 levels via cardiac release in the mechanism.

β‐Adrenoceptor activation affects galectin‐3 as a biomarker and therapeutic target in heart disease

“…Administration of isoprenaline to wild‐type mice induced parallel increases in cardiac and circulating content of Gal‐3, which can be effectively inhibited by β‐adrenoceptor antagonists (Nguyen et al, ). Interestingly, in the Mst1‐TG mice without increase in the circulating Gal‐3 level at basal conditions, isoprenaline treatment for 2 days markedly increased circulating levels of Gal‐3, implying a “permissive” role of β‐adrenoceptor activation in mediating expansion of the “extracellular Gal‐3 pool” and cardiac release of Gal‐3 in this DCM model (Figure ; Nguyen, Su, Vizi, et al, ).…”

“…These findings suggest the presence of a non‐releasable “intracellular Gal‐3 pool” and a releasable “extracellular Gal‐3 pool” (Figure ). The proposed existence of two different Ga‐3 pools may be helpful to explain the findings from the DCM model of Mst1‐TG mice, in which cardiac Gal‐3 content is markedly elevated without change in circulation levels of Gal‐3, relative to control mice (Nguyen, Su, Vizi, et al, ), suggesting the absence of the “extracellular pool.” In contrast, in other disease models studied, cardiac content of Gal‐3 is in proportion to the increment of circulating Gal‐3 levels, indicating the presence of both Gal‐3 pools leading to cardiac Gal‐3 spillover into the circulation (Nguyen, Su, Vizi, et al, ). Administration of isoprenaline to wild‐type mice induced parallel increases in cardiac and circulating content of Gal‐3, which can be effectively inhibited by β‐adrenoceptor antagonists (Nguyen et al, ).…”

“…Under conditions of cardiac pressure overload or MI, histological examination showed that increased Gal‐3 expression is mainly due to regional inflammatory cells and fibroblasts (Frunza et al, ; Yu et al, ). Cardiomyocytes express ample amounts of β‐adrenoceptors and activation of these receptors by pharmacological and genetic means is known to promote cardiomyocyte death, myocardial inflammation, and fibrosis (Engelhardt et al, ; Hartupee & Mann, ; Nguyen, Su, Vizi, et al, ; Xiao et al, ; Xu et al, ). In this regard, inflammatory cells express β‐adrenoceptors (β 2 ‐adrenoceptors are the predominant subtype) and there is evidence for activation of inflammatory cells mediated by β 2 ‐adrenoceptors (Padro & Sanders, ).…”

“…In this regard, inflammatory cells express β‐adrenoceptors (β 2 ‐adrenoceptors are the predominant subtype) and there is evidence for activation of inflammatory cells mediated by β 2 ‐adrenoceptors (Padro & Sanders, ). Following a short‐term stimulation with isoprenaline or in β 2 ‐TG mice, up‐regulation of cardiac Gal‐3 expression is derived from cardiomyocytes, in addition to inflammatory cells and fibroblasts (Nguyen, Su, Kiriazis, et al, ; Nguyen, Su, Vizi, et al, ; Nguyen et al, ). This is particularly the case for the Mst1‐TG model of DCM with very high cardiac Gal‐3 content and interstitial fibrosis without inflammatory cell infiltration (Nguyen, Su, Vizi, et al, ; Nguyen et al, ).…”

“…With its expression significantly and rapidly induced under diseased conditions, Gal‐3 has received great interest over other galectins for its role in a variety of pathological conditions including cancer, diabetes, inflammation, and heart disease (Figure ). In almost all animal models of heart disease studied so far, cardiac Gal‐3 expression is up‐regulated (Calvier et al, ; Frunza et al, ; Gonzalez et al, , ; Nguyen, Su, Vizi, et al, ; Vergaro et al, ; Yu et al, ). Current development of anti‐Gal‐3 drugs is to target the CRD to neutralize Gal‐3 from binding with glycoproteins (Table ).…”