Inhibition of miR-208b improves cardiac function in titin-based dilated cardiomyopathy
Qifeng Zhou, Sonja Schötterl, Daniel Backes, Eva Brunner, Julia Kelley Hahn, Elena Ionesi, Parwez Aidery, Carsten Sticht, Siegfried Labeit, Reinhard Kandolf, Meinrad Gawaz, Michael GramlichInternational Journal of Cardiology2017
Background: Dilated cardiomyopathy (DCM) is the result of maladaptive cardiac remodeling, which involves microRNA regulation. In turn, microRNAs can contribute to the remodeling process by post-transcriptional modulation of gene expression networks. The exact role of microRNAs in the pathogenesis of DCM is largely unknown. Here, we used an inducible DCM mouse model that carries a human truncation mutation in the sarcomeric protein titin to dissect microRNA pathways in DCMdevelopment. Methods and results: MicroRNA microarray studies revealed up-regulation of microRNA-208b in themyocardium of DCMmice and DCMpatients (p b 0.05 compared to controls). In order to investigate the effect of microRNA- 208b on cardiac remodeling, loss-of-function and gain-of-function studies were performed by repetitive injec- tions of LNA-modified microRNA-208b mimics and antimiR-208b. MiR-208b overexpression resulted in cardiac hypertrophy, whereas miR-208b antagonisation prevented transition of adaptive to maladaptive remodeling in the DCMmousemodel. In vitro studies identified several pro-hypertrophic transcription factors as potential tar- gets of miR-208b, suggesting that microRNA-208b plays an important role in cardiac development and growth. MiR-208bwas also upregulated inDCMpatients, but not in heart failure patients due to ischemic heart disease or myocarditis. Conclusion: Our data suggests that miR-208b is involved in the remodeling process and pathogenesis of DCMby post-transcriptional gene expression modulation. MicroRNA-208b might be a novel therapeutic target for DCM.