MicroRNA-145 repairs infarcted myocardium by accelerating cardiomyocyte autophagy

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 309; no. 11; p. H1813
• Main Authors: Higashi, Kenshi, Yamada, Yoshihisa, Minatoguchi, Shingo, Baba, Shinya, Iwasa, Masamitsu, Kanamori, Hiromitsu, Kawasaki, Masanori, Nishigaki, Kazuhiko, Takemura, Genzou, Kumazaki, Minami, Akao, Yukihiro, Minatoguchi, Shinya
• Format: Journal Article
• Language: English
• Published: United States 01-12-2015
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Autophagy; Cell Line; Disease Models, Animal; Genetic Therapy - methods; Kruppel-Like Transcription Factors - metabolism; Male; MicroRNAs - administration & dosage; MicroRNAs - genetics; MicroRNAs - metabolism; Microtubule-Associated Proteins - metabolism; Myocardial Infarction - genetics; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Myocardial Infarction - therapy; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Rabbits; Rats; RNA Interference; RNA, Messenger - metabolism; Signal Transduction; Time Factors; Transfection; Ventricular Function, Left; Ventricular Remodeling; autophagy; cardiomyocyte; miR-145; myocardial infarction
• ISSN: 1522-1539
• DOI: 10.1152/ajpheart.00709.2014

We investigated whether microRNA-145 (miR-145) has a cardioprotective effect in a rabbit model of myocardial infarction (MI) and in H9c2 rat cardiomyoblasts. Rabbits underwent 30 min of coronary occlusion, followed by 2 days or 2 wk of reperfusion. Control microRNA (control group; 2.5 nmol/kg, n = 10) or miR-145 (miR-145 group, 2.5 nmol/kg, n = 10) encapsulated in liposomes was intravenously administered immediately after the start of reperfusion. H9c2 rat cardiomyoblasts were transfected with miR-145. The MI size was significantly smaller in the miR-145 group than in the control group at 2 days and 2 wk post-MI. miR-145 had improved the cardiac function and remodeling at 2 wk post-MI. These effects were reversed by chloroquine. Western blot analysis showed that miR-145 accelerated the transition of LC3B I to II and downregulated p62/SQSTM1 at 2 days or 2 wk after MI, but not at 4 wk, and activated Akt in the ischemic area at 2 days after MI. miR-145 inhibited the growth of H9c2 cells, accelerated the transition of LC3B I to II, and increased phosphorylated Akt in the H9c2 cells at 2 days after miR-145 transfection. Antagomir-145 significantly abolished the morphological change, the transition of LC3B I to II, and the increased phosphorylated Akt induced by miR-145 in H9c2 cells. We determined fibroblast growth factor receptor substrate 2 mRNA to be a target of miR-145, both in an in vivo model and in H9c2 cells. In conclusion, post-MI treatment with miR-145 protected the heart through the induction of cardiomyocyte autophagy by targeting fibroblast growth factor receptor substrate 2.