Inhibition of Galectin-3 Pathway Prevents Isoproterenol-Induced Left Ventricular Dysfunction and Fibrosis in Mice

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 67; no. 3; pp. 606 - 612
• Main Authors: Vergaro, Giuseppe, Prud’homme, Mathilde, Fazal, Loubina, Merval, Regine, Passino, Claudio, Emdin, Michele, Samuel, Jane-Lise, Cohen Solal, Alain, Delcayre, Claude
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.03.2016
• Subjects: Animals; Disease Models, Animal; Echocardiography; Fibrosis; Galectin 3 - antagonists & inhibitors; Galectin 3 - biosynthesis; Galectin 3 - genetics; Gene Expression Regulation; Heart Ventricles - pathology; Heart Ventricles - physiopathology; Isoproterenol - toxicity; Male; Mice; Mice, Transgenic; Myocardium - metabolism; Myocardium - pathology; RNA - genetics; Signal Transduction; Ventricular Dysfunction, Left - chemically induced; Ventricular Dysfunction, Left - diagnosis; Ventricular Dysfunction, Left - genetics; fibrosis; isoproterenol; inflammation; galectin-3; aldosterone; heart
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.115.06161

Galectin-3 (Gal-3) is involved in inflammation, fibrogenesis, and cardiac remodeling. Previous evidence shows that Gal-3 interacts with aldosterone in promoting macrophage infiltration and vascular fibrosis and that Gal-3 genetic and pharmacological inhibition prevents remodeling in a pressure-overload animal model of heart failure. We aimed to explore the contribution of Gal-3 and aldosterone in mechanisms leading to heart failure in a murine model. Male mice with cardiac-specific hyperaldosteronism underwent isoproterenol subcutaneous injections, to be then randomized to receive placebo, a Gal-3 inhibitor (modified citrus pectin [MCP]), an aldosterone antagonist (potassium canrenoate), or MCP+canrenoate for 14 days. Isoproterenol induced a rapid and persistent decrease in left ventricular fractional shortening (−20% at day 14); this was markedly improved by treatment with either MCP or canrenoate (both P<0.001 versus placebo). MCP and canrenoate also reduced cardiac hypertrophy and fibrosis and the expression of genes involved in fibrogenesis (Coll-1 and Coll-3) and macrophage infiltration (CD-68 and MCP-1). After isoproterenol, Gal-3 gene expression (P<0.05 versus placebo) and protein levels (−61% and −69% versus placebo) were decreased by both canrenoate and MCP. The combined use of antagonists of Gal-3 and aldosterone resulted in more pronounced effects on cardiac hypertrophy, inflammation, and fibrosis, when compared with either MCP or canrenoate alone. Inhibition of Gal-3 and aldosterone can reverse isoproterenol-induced left ventricular dysfunction, by reducing myocardial inflammation and fibrogenesis. Gal-3 likely participates in mechanisms of aldosterone-mediated myocardial damage in a heart failure murine model with cardiac hyperaldosteronism. Gal-3 inhibition may represent a new promising therapeutic option in heart failure.