Up-regulation of MicroRNA-21 Mediates Isoflurane-induced Protection of Cardiomyocytes

• Published in: Anesthesiology (Philadelphia) 2015-04, Vol.122 (4), p.795-805
• Main Authors: Olson, Jessica M, Yan, Yasheng, Bai, Xiaowen, Ge, Zhi-Dong, Liang, Mingyu, Kriegel, Alison J, Twaroski, Danielle M, Bosnjak, Zeljko J
• Format: Article
• Language: English
• Subjects: Anesthetics, Inhalation - pharmacology; Animals; Animals, Newborn; Cardiotonic Agents - pharmacology; Cells, Cultured; Female; Isoflurane - pharmacology; Male; Mice; Mice, Knockout; MicroRNAs - biosynthesis; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Pregnancy; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Up-Regulation - drug effects; Up-Regulation - physiology
• ISSN: 0003-3022; 1528-1175
• DOI: 10.1097/ALN.0000000000000567

BACKGROUND:Anesthetic cardioprotection reduces myocardial infarct size after ischemia–reperfusion injury. Currently, the role of microRNA in this process remains unknown. MicroRNAs are short, noncoding nucleotide sequences that negatively regulate gene expression through degradation or suppression of messenger RNA. In this study, the authors uncovered the functional role of microRNA-21 (miR-21) up-regulation after anesthetic exposure. METHODS:MicroRNA and messenger RNA expression changes were analyzed by quantitative real-time polymerase chain reaction in cardiomyocytes after exposure to isoflurane. Lactate dehydrogenase release assay and propidium iodide staining were conducted after inhibition of miR-21. miR-21 target expression was analyzed by Western blot. The functional role of miR-21 was confirmed in vivo in both wild-type and miR-21 knockout mice. RESULTS:Isoflurane induces an acute up-regulation of miR-21 in both in vivo and in vitro rat models (n = 6, 247.8 ± 27.5% and 258.5 ± 9.0%), which mediates protection to cardiomyocytes through down-regulation of programmed cell death protein 4 messenger RNA (n = 3, 82.0 ± 4.9% of control group). This protective effect was confirmed by knockdown of miR-21 and programmed cell death protein 4 in vitro. In addition, the protective effect of isoflurane was abolished in miR-21 knockout mice in vivo, with no significant decrease in infarct size compared with nonexposed controls (n = 8, 62.3 ± 4.6% and 56.2 ± 3.2%). CONCLUSIONS:The authors demonstrate for the first time that isoflurane mediates protection of cardiomyocytes against oxidative stress via an miR-21/programmed cell death protein 4 pathway. These results reveal a novel mechanism by which the damage done by ischemia/reperfusion injury may be decreased.