期刊
HYPERTENSION
卷 71, 期 2, 页码 280-288出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.117.10094
关键词
cardiomyopathies; fibroblasts; heart failure; microRNAs
资金
- Dutch Heart Foundation [2014T105]
- Netherlands Organization for Scientific Research [NWO Vidi 91714363]
- Netherlands CardioVascular Research Initiative
- Dutch Heart Foundation
- Dutch Federation of University Medical Centers
- Netherlands Organization for Health Research and Development (ZonMW)
- Royal Netherlands Academy of Sciences (CVON-ARENA)
- European Union Commission's Seventh Framework program under grant Marie-Curie Industry Academy Pathways and Partnerships [CARDIOMIR 285991]
- European Research Council [311549]
- Institute of Health Carlos III, Spanish Ministry of Economy and Competitiveness of Spain [CB16/11/00483, PI1501909]
- FEDER
- [602904]
- European Research Council (ERC) [311549] Funding Source: European Research Council (ERC)
Pressure overload causes cardiac fibroblast activation and transdifferentiation, leading to increased interstitial fibrosis formation and subsequently myocardial stiffness, diastolic and systolic dysfunction, and eventually heart failure. A better understanding of the molecular mechanisms underlying pressure overload-induced cardiac remodeling and fibrosis will have implications for heart failure treatment strategies. The microRNA (miRNA)-221/222 family, consisting of miR-221-3p and miR-222-3p, is differentially regulated in mouse and human cardiac pathology and inversely associated with kidney and liver fibrosis. We investigated the role of this miRNA family during pressure overload-induced cardiac remodeling. In myocardial biopsies of patients with severe fibrosis and dilated cardiomyopathy or aortic stenosis, we found significantly lower miRNA-221/222 levels as compared to matched patients with nonsevere fibrosis. In addition, miRNA-221/222 levels in aortic stenosis patients correlated negatively with the extent of myocardial fibrosis and with left ventricular stiffness. Inhibition of both miRNAs during AngII (angiotensin II)-mediated pressure overload in mice led to increased fibrosis and aggravated left ventricular dilation and dysfunction. In rat cardiac fibroblasts, inhibition of miRNA-221/222 derepressed TGF-beta (transforming growth factor-beta)-mediated profibrotic SMAD2 (mothers against decapentaplegic homolog 2) signaling and downstream gene expression, whereas overexpression of both miRNAs blunted TGF-beta-induced profibrotic signaling. We found that the miRNA-221/222 family may target several genes involved in TGF-beta signaling, including JNK1 (c-Jun N-terminal kinase 1), TGF-beta receptor 1 and TGF-beta receptor 2, and ETS-1 (ETS proto-oncogene 1). Our findings show that heart failure-associated downregulation of the miRNA-221/222 family enables profibrotic signaling in the pressure-overloaded heart.
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