期刊
THERANOSTICS
卷 6, 期 12, 页码 2068-2083出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.15007
关键词
cardiac fibrosis; miR-433; AZIN1; JNK1
资金
- National Natural Science Foundation of China [81570362, 81200169, 81370332, 81170201, 81270314, 81470515, 81472158, 81400647, 81370362]
- Priority Academic Program Development of Jiangsu Higher Education Institutions [PAPD20102013]
- National Basic Research Program of China [2014CB542300]
- National Major Research Plan Training Program [91339108]
- Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant [20152509]
- Shanghai Medical Guide Project from Shanghai Science and Technology Committee [134119a3000]
- Natural Science Foundation of Shanghai [14ZR1437900]
- Netherlands Cardiovascular Research Initiative (CVON): the Dutch Heart Foundation
- Dutch Federation of University Medical Centers
- Netherlands Organization for Health Research and Development
- Royal Netherlands Academy of Science
- National Institutes of Health (NCATS) [UH3 TR000901]
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UH3TR000901] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL122547] Funding Source: NIH RePORTER
Dysregulation of microRNAs has been implicated in many cardiovascular diseases including fibrosis. Here we report that miR-433 was consistently elevated in three models of heart disease with prominent cardiac fibrosis, and was enriched in fibroblasts compared to cardiomyocytes. Forced expression of miR-433 in neonatal rat cardiac fibroblasts increased proliferation and their differentiation into myofibroblasts as determined by EdU incorporation, alpha-SMA staining, and expression levels of fibrosis-associated genes. Conversely, inhibition of miR-433 exhibited opposite results. AZIN1 and JNK1 were identified as two target genes of miR-433. Decreased level of AZIN1 activated TGF-beta 1 while down-regulation of JNK1 resulted in activation of ERK and p38 kinase leading to Smad3 activation and ultimately cardiac fibrosis. Importantly, systemic neutralization of miR-433 or adeno-associated virus 9 (AAV9)-mediated cardiac transfer of a miR-433 sponge attenuated cardiac fibrosis and ventricular dysfunction following myocardial infarction. Thus, our work suggests that miR-433 is a potential target for amelioration of cardiac fibrosis.
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