MiR-125b Is Critical for Fibroblast-to-Myofibroblast Transition and Cardiac Fibrosis.
MiR-125b Is Critical for Fibroblast-to-Myofibroblast Transition and Cardiac Fibrosis.
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DOI：
10.1161/circulationaha.115.018174
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发表时间：
2016-01-19
期刊：
影响因子：
37.8
通讯作者：
Vaughan DE
中科院分区：
文献类型：
--
作者：
Nagpal V;Rai R;Place AT;Murphy SB;Verma SK;Ghosh AK;Vaughan DE
Cardiac fibrosis is the pathological consequence of stress-induced fibroblast proliferation and fibroblast-to-myofibroblast transition (FMT). MicroRNAs have been shown to play a central role in the pathogenesis of cardiac fibrosis. We identified a novel miRNA-driven mechanism that promotes cardiac fibrosis via regulation of multiple fibrogenic pathways. Using a combination of in vitro and in vivo studies, we identified that miR-125b is a novel regulator of cardiac fibrosis, proliferation and activation of cardiac fibroblasts. We demonstrate that miR-125b is induced in both fibrotic human heart and murine models of cardiac fibrosis. In addition, our results indicate that miR-125b is necessary and sufficient for the induction of FMT by functionally targeting apelin, a critical repressor of fibrogenesis. Furthermore, we observed that miR-125b inhibits p53 to induce fibroblast proliferation. Most importantly, in vivo silencing of miR-125b by systemic delivery of locked nucleic acid (LNA) rescued Angiotensin II-induced perivascular and interstitial fibrosis. Finally, the RNA-sequencing analysis established that miR-125b altered the gene expression profiles of the key fibrosis-related genes and is a core component of fibrogenesis in the heart. In conclusion, miR-125b is critical for induction of cardiac fibrosis and acts as a potent repressor of multiple anti-fibrotic mechanisms. Inhibition of miR-125b may represent a novel therapeutic approach for the treatment of human cardiac fibrosis and other fibrotic diseases.
