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

Abstract

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.

Novel heart failure biomarkers: why do we fail to exploit their potential?

“…Many clinical association studies have shown that plasma levels of Gal-3 are associated with cardiac function and LV-filling pressures [45,46]. Moreover, studies in animal models of HF revealed that Gal-3 was involved in cardiac remodeling, and both genetic disruption and pharmacological inhibition of Gal-3 resulted in reduced cardiac remodeling, including myocardial fibrosis [43,[47][48][49][50][51][52]. However, because HF is a multi-organ syndrome, other organs could also contribute to increased Gal-3 levels in HF.…”

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

“…Experimental studies in vitro and in vivo have yielded several lines of evidence for Gal-3 as a mediator of heart disease. First, when tested ex vivo, Gal-3 promoted fibroblast proliferation and expression of fibrogenic genes (Frunza et al, 2016;Ibarrola et al, 2018;Mackinnon et al, 2012;Takemoto et al, 2016;Vergaro et al, 2016;Yu et al, 2013). Gal-3 also promoted the innate immune response by stimulating monocyte migration and expression of inflammatory cytokines and chemokines (Jaquenod De Giusti et al, 2015;Nachtigal et al, 2008;Sharma et al, 2004;Vasta, 2012).…”

Efficacy and safety of two dosages of canrenone as add‐on therapy in hypertensive patients taking ace‐inhibitors or angiotensin II receptor blockers and hydrochlorothiazide at maximum dosage in a randomized clinical trial: The ESCAPE‐IT trial

“…Galactine‐3 is a pleiotropic lectin with an important role in cell proliferation, adhesion, differentiation, angiogenesis, and apoptosis. Galectin‐3 activates many profibrotic factors, promotes fibroblast proliferation and transformation, and mediates collagen production . Higher levels of galectine‐3 have been associated with a worse prognosis in patients with acute respiratory distress syndrome .…”