Abstract
Mitochondrial DNA contains unmethylated cytidine-phosphate-guanosine motif, and is recognized by Toll-like receptor (TLR) 9, inducing sterile inflammation. We previously reported that the accumulation of mitochondrial DNA in cardiomyocytes induces myocardial inflammation and heart failure using an animal model. (Nature 2012) In this study, to investigate the effect of inhibition of the inflammation via TLR9 induced by mitochondrial DNA accumulation on heart failure, we examined whether a TLR9 inhibitor, E6446 (6-[3-(pyrrolidin-1-yl)propoxy)-2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl]benzo[d]oxazole), prevents the development and progression of heart failure in mice. In in vitro study, isolated cardiomyocytes were stimulated by a TLR9 ligand (ODN1668) in the presence of E6446. ODN1668 significantly increased the expression levels of inflammatory cytokine mRNAs in the cells. Incubation of cardiomyocytes with E6446 significantly reduced the level of those mRNAs induced by ODN1668. CCCP increased the number of autolysosomes with DNA accumulation. Although E6446 had no effect on the number of the autolysosomes, it significantly reduced the production of inflammatory cytokine mRNAs induced by CCCP in cardiomyocytes. In in vivo study, mice orally received E6446 or saline 2 days before transverse aortic constriction (TAC) and every two days for 4 weeks thereafter. Four weeks after TAC, chamber size and fractional shortening (FS) of left ventricle (LV) and lung weight were significantly reduced in E6446 group compared to saline group. Furthermore, the infiltration of inflammatory cells including macrophages in the TAC-operated heart was inhibited by E6446. Next, mice with LV dysfunction at 2 weeks after TAC were subjected to the oral administration with E6446 or saline every two days for 4 weeks. The LV chamber size was significantly smaller and FS was higher in E6446 group than those in saline group 6 weeks after TAC. Our study showed that E6446 prevented the development of LV dilatation and dysfunction with inflammation and slowed progression of cardiac remodeling induced by pressure overload. E6446 might be a novel therapeutic to treat patients with heart failure.
Published Version
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