MicroRNA-101 inhibited postinfarct cardiac fibrosis and improved left ventricular compliance via the FBJ osteosarcoma oncogene/transforming growth factor-β1 pathway
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Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
Zhenwei Pan1, Xuelin Sun, Hongli Shan
1Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.
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-β1. 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-β1 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.
Insights
MicroRNA-101a (miR-101a) reduces cardiac fibrosis and improves heart function after myocardial infarction. This study shows miR-101a targets c-Fos, offering therapeutic potential for fibrotic heart disease.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Fibrosis Research
Background:
- Cardiac interstitial fibrosis impairs heart function in chronic myocardial infarction.
- MicroRNAs (miRs) are emerging regulators of cardiovascular diseases, including fibrosis.
Purpose of the Study:
- To investigate the role of miR-101 in cardiac fibrosis.
- To elucidate the underlying molecular mechanisms of miR-101 action.
Main Methods:
- Assessed miR-101a/b expression in post-myocardial infarction rat models.
- Utilized cultured cardiac fibroblasts to study miR-101a/b effects on proliferation and collagen production.
- Investigated c-Fos as a direct target of miR-101a.
- Employed adenovirus-mediated miR-101a overexpression in vivo.
Main Results:
- miR-101a/b expression decreased in peri-infarct areas and was suppressed by angiotensin II.
- Forced miR-101a/b expression inhibited fibroblast proliferation and collagen synthesis.
- miR-101a directly targeted c-Fos, reducing its mRNA and protein levels.
- Overexpression of miR-101a improved cardiac performance and reduced fibrosis in post-infarct rats, inhibiting c-Fos and TGF-β1.
Conclusions:
- miR-101a overexpression alleviates cardiac interstitial fibrosis and improves cardiac function post-myocardial infarction.
- miR-101a demonstrates significant therapeutic potential for treating fibrotic heart diseases.
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