Abstract 13413: Improved Healing by Immediate Selective Mineralocorticoid Receptor Antagonism After Experimental Myocardial Infarction: Modulation of Monocyte Subset Dynamics and MicroRNA Dysregulation
Mineralocorticoid receptor (MR) blockade improves outcome in patients with left ventricular (LV) dysfunction after myocardial infarction (MI); however, the underlying mechanisms are still under investigation. This study examined whether MR antagonism promotes healing of the infarcted myocardium via effects on monocyte heterogeneity and microRNA dysregulation. Starting immediately after coronary ligation, C57BL/6J mice were treated with the selective MR antagonist eplerenone (100 mg/kg per day by gavage) or placebo. At 7 days, eplerenone therapy versus placebo significantly prevented LV chamber enlargement and functional deterioration, reduced thinning and dilatation of the infarcted wall, and enhanced neovessel formation at the site of ischemic injury. At days 2 and 3 post-MI, MR blockade led to a shift in the balance between monocyte subsets toward the Ly6C(lo) subset in the spleen and peripheral blood. Multicolor flow cytometry revealed predominant infiltration of Ly6C(hi) monocytes in the healing myocardium of placebo-treated mice at the same time. In contrast, MR blockade led to a significant infiltration of Ly6C(lo) monocytes and an increased ratio of healing promoting Ly6C(lo) monocytes to pro-inflammatory Ly6C(hi) in the infarcted myocardium. In addition, microRNA (miRNA) expression profiling in the infarct zone revealed that MR antagonism prevented the deregulation of several miRNAs (i.e. miR-1,-30,-133,-378,-499) involved in cardiac healing and remodeling early after ischaemia (Figure). In conclusion, our data suggest that immediate MR antagonism exerts its beneficial effects on early healing processes post MI by modulating monocyte polarization as well as miRNA regulation in the infarct wound. Figure: Volcano plot with significant (P<0.05) pairwise comparisons (PC) of miRNAs of placebo scar (3 days after MI) vs sham, fold change (FC)>1.4 and corrispective miRNA PCs of eplerenone treatment.
- © 2012 by American Heart Association, Inc.