Abstract 2960: HuR Knockdown Attenuates Post-MI Left Ventricular Dysfunction and Remodeling via Enhanced mRNA Degradation of Pro-inflammatory Cytokines and Inhibition of P53-mediated Apoptosis and TGF-beta-mediated Fibrosis in IL-10 Knock-out Mice
Prolonged inflammatory response is associated with left ventricular (LV) dysfunction and adverse remodeling following myocardial infarction (MI). IL-10 inhibits inflammatory response by suppressing HuR-mediated mRNA stabilization of pro-inflammatory cytokines and attenuates post-MI LV dysfunction and remodeling. Following MI, IL-10 KO-mice showed increased infiltration of inflammatory cells in the border zone of the infarct with LV dysfunction, fibrosis and cardiomyocyte apoptosis. We tested if HuR knock-down attenuates these undesirable effects in IL-10 KO-mice. WT or IL-10 KO mice with MI were treated with intramyocardial injection of either control or HuR-specific RNAi. HuR knock-down significantly inhibited infiltration of inflammatory cells and mRNA expression of pro-inflammatory cytokines in the myocardium. Echocardiography showed that increased LV dysfunction (reduced %FS and %EF) in IL-10 KO-mice was significantly reversed by HuR knock-down. Increased inflammation in IL-10 KO mice was associated with increased cardiomyocyte apoptosis in the LV (p<0.01 vs. WT-mice). Interestingly, HuR knock-down significantly reduced p53-mediated cardiomyocyte apoptosis. Moreover, HuR knock-down significantly reduced infarct size and fibrosis area. Reduced fibrosis was associated with decrease in TGF-β expression in HuR knock-down mice. RNAi mediated HuR knock-down in mouse monocyte/macrophage cell line (RAW 264.7 cells) corroborated in vivo data and revealed reduced mRNA expression of TNF-alpha, TGF-beta, p53 and MMP-9. Furthermore, HuR knock-down in these cells significantly reduced LPS-mediated mRNA stabilization of the above genes. Taken together, our studies suggest that HuR is a direct target of IL-10 and HuR knockdown mimics anti-inflammatory effects of IL-10 including suppression of cytokine mRNA stability, fibrosis and cardiomyocyte apoptosis and in turn contributing to improved LV function and remodeling.
This research has received full or partial funding support from the American Heart Association, National Center.