Mineralocorticoid Receptor Antagonists Modulate Galectin-3 and Interleukin-33/ST2 Signaling in Left Ventricular Systolic Dysfunction After Acute Myocardial Infarction

OBJECTIVES This study aimed to evaluate the specific role of the 2 available mineralocorticoid receptor antagonists (MRAs), epterenone and spironolactone, on the modulation of gatectin-3 (Gal-3) and interteukin (IL)-33/ST2 signaling in an experimental model of left ventricular systolic dysfunction after acute myocardial infarction (MI). BACKGROUND The molecular mechanisms of benefits of MRAs in patients with left ventricular systolic dysfunction after MI not welt understood. METHODS MI and left ventricular systolic dysfunction were induced by permanent ligation of the anterior coronary artery in 45 mate Wistar rats, randomly assigned to no therapy (MI group, n = 15) or to receive MRAs (100 mg/kg/day) for 4 weeks; either epterenone (n = 15) or spironotactone (n = 15) was used. A sham group was used as a control (n = 8). Elements of the pathway for Gal-3 including transforming growth factor (TGF)-beta and SMAD3, as welt as that for IL-33/ST2 (including IL-33 and soluble ST2 [sST2]) were analyzed in the infarcted and noninfarcted myocardium by quantitative real-time reverse transcription potymerase chain reaction. Expression of markers of fibrosis (collagen types I and III, tissue inhibitor of metalloproteinase-1) and inflammation (IL-6, tumor necrosis factor-alpha, monocyte chemotactic protein-1) was also examined. RESULTS In the infarcted myocardium, compared with sham animals, the MI group had higher concentrations of Gal-3, TGF-beta, SMAD3, IL-33, and sST2, as welt as higher concentrations of markers of fibrosis and inflammation. Treatment with MRAs down-regulated Gal-3, TGF-beta, and SMAD3 and enhanced IL-33/ST2 signaling with tower expression of sST2; protective IL-33 up-regulation was unaffected by MRAs. Modulation of Gal-3 and IL-33/ST2 signaling induced by MRAs correlated with lower expression levels of fibrosis and inflammatory markers. No differences were found between epterenone and spironotactone. In the noninfarcted myocardium, compared with sham animals, the MI group exhibited a higher expression of Gal-3 and IL-33, but no signs of inflammation or fibrosis were observed; in the presence of MRAs, IL-33 expression was significantly up-regulated, but Gal-3 was unaffected. CONCLUSIONS MRAs play a pivotal rote in the Gal-3 and IL-33/ST2 modulation in post-MI cardiac remodeling. (C) 2015 by the American College of Cardiology Foundation.