MicroRNA-101 Inhibited Postinfarct Cardiac Fibrosis and Improved Left Ventricular Compliance via the FBJ Osteosarcoma Oncogene/Transforming Growth Factor-β1 Pathway

Abstract

Background-Cardiac interstitial fibrosis is a major cause of the deteriorated performance of the heart in patients with chronic myocardial infarction. MicroRNAs (miRs) have recently been proven to be a novel class of regulators of cardiovascular diseases, including those associated with cardiac fibrosis. This study aimed to explore the role of miR-101 in cardiac fibrosis and the underlying mechanisms. Methods and Results-Four weeks after coronary artery ligation of rats, the expression of miR-101a and miR-101b(miR-101a/b) in the peri-infarct area was decreased. Treatment of cultured rat neonatal cardiac fibroblasts with angiotensin II also suppressed the expression of miR-101a/b. Forced expression of miR-101a/b suppressed the proliferation and collagen production in rat neonatal cardiac fibroblasts, as revealed by cell counting, MTT assay, and quantitative reverse transcription-polymerase chain reaction. The effect was abrogated by cotransfection with AMO-101a/b, the antisense inhibitors of miR-101a/b. c-Fos was found to be a target of miR-101a because overexpression of miR-101a decreased the protein and mRNA levels of c-Fos and its downstream protein transforming growth factor-␤1. Silencing c-Fos by siRNA mimicked the antifibrotic action of miR-101a, whereas forced expression of c-Fos protein canceled the effect of miR-101a in cultured cardiac fibroblasts. Strikingly, echocardiography and hemodynamic measurements indicated remarkable improvement of the cardiac performance 4 weeks after adenovirus-mediated overexpression of miR-101a in rats with chronic myocardial infarction. Furthermore, the interstitial fibrosis was alleviated and the expression of c-Fos and transforming growth factor-␤1 was inhibited. Conclusion-Overexpression of miR-101a can mitigate interstitial fibrosis and the deterioration of cardiac performance in postinfarct rats, indicating the therapeutic potential of miR-101a for cardiac disease associated with fibrosis. (Circulation. 2012;126:840-850.)

Transforming Growth Factor‐β Receptor III is a Potential Regulator of Ischemia‐Induced Cardiomyocyte Apoptosis

“…The infarct size after 24 hours of MI was decreased to 32.5±3.0% ( P <0.05) in AAV‐shTGFβR3 mice (Figure 7C). We examined the heart function after 4 weeks of MI because several reports have shown that the muridae ischemia heart shows characteristics of heart failure at this time point 5, 17. Fractional shortening and ejection fraction were significantly improved in AAV‐shTGFβR3 mice compared with AAV‐scramble mice (Figure 7D and 7E).…”

miRNome in myocardial infarction: Future directions and perspective

“…Anti-fibrotic action of miR-101a was mimicked by silencing c-Fos using siRNA, whereas effect of miR-101a in cultured CFs was cancelled by enforced expression of the c-Fos. In rats with chronic MI, four weeks after overexpression of miR-101a using adenovirus, remarkable improvement in cardiac performance was observed as well as reduction in interstitial fibrosis and inhibition of c-Fos and TGF-β1 expression [50] . Pioglitazone was further shown to increase miR-711 expression and significantly reduce collagen-Ⅰ levels similar to CFs, and overexpression of miR-711 suppressed collagen-Ⅰ levels.…”

microRNAs in cardiovascular disease – clinical application

“…At the moment, there is no data available from clinical trials evaluating the therapeutic clinical deployment of miRNAs in CVD. In vitro studies and animal models, though, have produced promising results with potential for a future clinical application [144][145][146][147][148]. Here, we provide an example on how miRNAs could effectively and useful be applied in a clinical setting:…”