title: Inhibition of Galectin-3 Pathway Prevents Isoproterenol-Induced Left Ventricular Dysfunction and Fibrosis in Mice.
abstract: 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.
authors.affiliation: From INSERM U942 and Université Paris-Diderot, Paris, France (G.V., M.P., L.F., R.M., J.-L.S., A.C.S., C.D.); Institute of Life Sciences, Scuola Superiore Sant'Anna di Pisa, Pisa, Italy (G.V., C.P., M.E.); and Cardiology and Cardiovascular Medicine Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy (G.V., C.P., M.E.). vergaro@ftgm.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Vergaro
authors.affiliation: From INSERM U942 and Université Paris-Diderot, Paris, France (G.V., M.P., L.F., R.M., J.-L.S., A.C.S., C.D.); Institute of Life Sciences, Scuola Superiore Sant'Anna di Pisa, Pisa, Italy (G.V., C.P., M.E.); and Cardiology and Cardiovascular Medicine Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy (G.V., C.P., M.E.).
authors.forename: Mathilde
authors.initials: M
authors.lastname: Prud'homme
authors.affiliation: From INSERM U942 and Université Paris-Diderot, Paris, France (G.V., M.P., L.F., R.M., J.-L.S., A.C.S., C.D.); Institute of Life Sciences, Scuola Superiore Sant'Anna di Pisa, Pisa, Italy (G.V., C.P., M.E.); and Cardiology and Cardiovascular Medicine Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy (G.V., C.P., M.E.).
authors.forename: Loubina
authors.initials: L
authors.lastname: Fazal
authors.affiliation: From INSERM U942 and Université Paris-Diderot, Paris, France (G.V., M.P., L.F., R.M., J.-L.S., A.C.S., C.D.); Institute of Life Sciences, Scuola Superiore Sant'Anna di Pisa, Pisa, Italy (G.V., C.P., M.E.); and Cardiology and Cardiovascular Medicine Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy (G.V., C.P., M.E.).
authors.forename: Regine
authors.initials: R
authors.lastname: Merval
authors.affiliation: From INSERM U942 and Université Paris-Diderot, Paris, France (G.V., M.P., L.F., R.M., J.-L.S., A.C.S., C.D.); Institute of Life Sciences, Scuola Superiore Sant'Anna di Pisa, Pisa, Italy (G.V., C.P., M.E.); and Cardiology and Cardiovascular Medicine Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy (G.V., C.P., M.E.).
authors.forename: Claudio
authors.initials: C
authors.lastname: Passino
authors.affiliation: From INSERM U942 and Université Paris-Diderot, Paris, France (G.V., M.P., L.F., R.M., J.-L.S., A.C.S., C.D.); Institute of Life Sciences, Scuola Superiore Sant'Anna di Pisa, Pisa, Italy (G.V., C.P., M.E.); and Cardiology and Cardiovascular Medicine Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy (G.V., C.P., M.E.).
authors.forename: Michele
authors.initials: M
authors.lastname: Emdin
authors.affiliation: From INSERM U942 and Université Paris-Diderot, Paris, France (G.V., M.P., L.F., R.M., J.-L.S., A.C.S., C.D.); Institute of Life Sciences, Scuola Superiore Sant'Anna di Pisa, Pisa, Italy (G.V., C.P., M.E.); and Cardiology and Cardiovascular Medicine Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy (G.V., C.P., M.E.).
authors.forename: Jane-Lise
authors.initials: JL
authors.lastname: Samuel
authors.affiliation: From INSERM U942 and Université Paris-Diderot, Paris, France (G.V., M.P., L.F., R.M., J.-L.S., A.C.S., C.D.); Institute of Life Sciences, Scuola Superiore Sant'Anna di Pisa, Pisa, Italy (G.V., C.P., M.E.); and Cardiology and Cardiovascular Medicine Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy (G.V., C.P., M.E.).
authors.forename: Alain
authors.initials: A
authors.lastname: Cohen Solal
authors.affiliation: From INSERM U942 and Université Paris-Diderot, Paris, France (G.V., M.P., L.F., R.M., J.-L.S., A.C.S., C.D.); Institute of Life Sciences, Scuola Superiore Sant'Anna di Pisa, Pisa, Italy (G.V., C.P., M.E.); and Cardiology and Cardiovascular Medicine Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy (G.V., C.P., M.E.).
authors.forename: Claude
authors.initials: C
authors.lastname: Delcayre
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004452:Echocardiography; D005355:Fibrosis; D037502:Galectin 3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000473:pathology* / Q000503:physiopathology; D007545:Isoproterenol / Q000633:toxicity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D012313:RNA / Q000235:genetics*; D015398:Signal Transduction; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000175:diagnosis / Q000235:genetics*
chemical_list: D037502:Galectin 3; D012313:RNA; D007545:Isoproterenol
keywords: aldosterone; fibrosis; galectin-3; heart; inflammation; isoproterenol