Abstract 5415: IL-10 Suppresses Pro-Inflammatory Cytokine Mediated Cardiac Dysfunction and Remodeling after Myocardial Infarction
Inflammation plays an important role in the pathogenesis of heart failure. Persistent inflammatory response has adverse effects on left ventricular (LV) function and remodeling following myocardial infarction (MI). We hypothesized that anti-inflammatory cytokine IL-10 treatment attenuates pro-inflammatory cytokine mediated cardiac dysfunction and remodeling, post-MI. Mice were treated with either saline or recombinant IL-10 (50μg/kg b.w) on 0,1,3,5 and 7 days after the induction of MI. Inflammatory response was assessed on day 3, LV functional and structural remodeling changes on 28 days post-MI. Infarct size (49%) was associated with increased infarct wall thinning in the control group. IL-10 treatment led to reduced infarct size (P<0.05) with increased wall thickness (P<0.01). Infiltration of inflammatory cells in the myocardium increased 3 days post-MI, which was significantly decreased after IL-10 treatment (P<0.01). MI- induced increase in the mRNA expression of various pro-inflammatory cytokines in the myocardium was significantly attenuated by IL-10 treatment (P<0.05). Increased post-MI pro-inflammatory cytokine release was associated with p38 MAP kinase activation and enhanced expression of TNF-alpha mRNA stabilizing protein, HuR. Interestingly, IL-10 treatment suppressed these effects. Echocardiography showed significantly improved left ventricular functions in IL-10 treated mice. Additionally, MI-induced increase in the expression and gelatinolytic activity of MMP-9 in control groups associated with increased fibrosis (P<0.01). Interestingly, IL-10 treatment reduced the MMP-9 activity with decreased fibrosis (P<0.05). Moreover, IL-10 treatment showed significantly higher capillary density in the border zone of infarct which was associated with enhanced STAT3 phosphorylation. Taken together, our studies demonstrate that IL-10 reduces severity of pro-inflammatory responses and contributes to improved heart function and remodeling by inhibiting pro-inflammatory cytokine expression, reduced cell infiltration and by modulating MMP-9, p38 MAPK and STAT3 signaling cascades.