title: Cardiac myocyte-protective effect of microRNA-22 during ischemia and reperfusion through disrupting the caveolin-3/eNOS signaling.
abstract: MicroRNA-22 (miR-22) was previously reported to elicit cardiac myocyte hypertrophy and had an anti-apoptotic effect on neurons. However, its effects on cardiac myocyte apoptosis and cardiac function during ischemia and reperfusion (I/R) are not clear. In the present study, we demonstrate that pre-administration of miR-22 mimic reduced I/R-induced cardiac dysfunction significantly in a rat model. We found that miR-22 overexpression inhibited cardiac myocyte apoptosis, and reduced cardiac remodeling during I/R. Significant cardiac myocyte apoptosis was also observed in a cardiac myocyte model after hypoxia/reoxygenation (H/R), a representative process of I/R. Further experiments showed that eNOS activity and the following NO production were significantly decreased during I/R and H/R, while such decrease was inhibited by overexpression of miR-22. Mechanistically, overexpression of miR-22 had little effect on the total protein level of eNOS, but restored the level of p-eNOS (Ser1177) which was down-regulated during H/R. Further RT-PCR results demonstrated that Caveolin 3 (Cav3), an upstream negative regulator of eNOS, was upregulated during H/R, resulting in a decrease of p-eNOS. However, such upregulation of Cav3 transcript level was inhibited directly by miR-22 during H/R, leading to a restored p-eNOS level and followed NO production in cardiac myocytes. Together, the present study revealed that miR-22 down-regulated Cav3, leading to restored eNOS activity and NO production, which further inhibited cardiac myocyte apoptosis and promoted cardiac function after I/R. Of clinical interest, the present study may highlight miR-22 as a potential therapeutic agent for reducing I/R induced cardiac injury.
authors.affiliation: Deparment of Vasculocardiology, The Second People's Hospital of Hefei Hefei 230011, Anhui, China.
authors.forename: Zhenfei
authors.initials: Z
authors.lastname: Chen
authors.affiliation: General Department of Hyperbaric Oxygen, The Second People's Hospital of Hefei Hefei 230011, Anhui, China.
authors.forename: Yinliang
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Deparment of Vasculocardiology, The Second People's Hospital of Hefei Hefei 230011, Anhui, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Gao
mesh_terms: D000818:Animals; D017209:Apoptosis; D051244:Caveolin 3 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D019610:Cytoprotection; D004195:Disease Models, Animal; D015536:Down-Regulation; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009841:Oligonucleotides / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017208:Rats, Wistar; D015398:Signal Transduction; D013318:Stroke Volume; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: C495549:Cav3 protein, rat; D051244:Caveolin 3; C580892:MIRN22 microRNA, rat; D035683:MicroRNAs; D009841:Oligonucleotides; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat
keywords: cardiac myocyte; caveolin-3; eNO; ischemia and reperfusion; microRNA-22