Inhibition of miR-208b improves cardiac function in titin-based dilated cardiomyopathy

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• 作者：Qifeng Zhou^a ; ¹ ; Sonja Schö ; tterl^a ; ¹ ; Daniel Backes^a ; Eva Brunner^b ; Julia Kelley Hahn^a ; Elena Ionesi^a ; Parwez Aidery^a ; Carsten Sticht^d ; Siegfried Labeit^c ; Reinhard Kandolf^b ; Meinrad Gawaz^a ; Michael Gramlich^a ; ^{michael.gramlich@med.uni-tuebingen.de}
• 关键词：Heart failure ; MicroRNA ; Cardiomyopathy ; Animal models of human disease ; Genetics ; Titin
• 刊名：International Journal of Cardiology
• 出版年：2017
• 出版时间：1 March 2017
• 年：2017
• 卷：230
• 期：Complete
• 页码：634-641
• 全文大小：2340 K
• 卷排序：230

文摘

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 DCM development.Methods and resultsMicroRNA microarray studies revealed up-regulation of microRNA-208b in the myocardium of DCM mice and DCM patients (p < 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 injections 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 DCM mouse model. In vitro studies identified several pro-hypertrophic transcription factors as potential targets of miR-208b, suggesting that microRNA-208b plays an important role in cardiac development and growth. MiR-208b was also upregulated in DCM patients, but not in heart failure patients due to ischemic heart disease or myocarditis.ConclusionOur data suggests that miR-208b is involved in the remodeling process and pathogenesis of DCM by post-transcriptional gene expression modulation. MicroRNA-208b might be a novel therapeutic target for DCM.