MiR-125b Is Critical for Fibroblast-to-Myofibroblast Transition and Cardiac Fibrosis. Issue 3 (19th January 2016)

• Record Type: Journal Article
• Authors: Nagpal, Varun; Rai, Rahul; Place, Aaron T.; Murphy, Sheila B.; Verma, Suresh K.; Ghosh, Asish K.; Vaughan, Douglas E.
• Is Part Of: Circulation. Volume 133:Issue 3(2016)
• Publication Date: 2016-01-19
• Subjects: angiotensin II -- fibrosis -- miR-125b -- RNA sequence -- transforming growth factor; Blood -- Circulation -- Periodicals; Cardiovascular system -- Periodicals; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; 616.1
• DOI: 10.1161/CIRCULATIONAHA.115.018174
• Languages: English
• ISSNs: 0009-7322

Abstract

Abstract : Background—: Cardiac fibrosis is the pathological consequence of stress-induced fibroblast proliferation and fibroblast-to-myofibroblast transition. 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. Methods and Results—: 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 fibroblast-to-myofibroblast transition 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 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. Conclusions—: 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. Abstract : Supplemental Digital Content is available in the text.