MicroRNA-21 Mediates Isoflurane-induced Cardioprotection against Ischemia-Reperfusion Injury via Akt/Nitric Oxide Synthase/Mitochondrial Permeability Transition Pore Pathway. Anesthesiology 2015 Oct;123(4):786-798
Date
08/11/2015Pubmed ID
26259139Pubmed Central ID
PMC4573345DOI
10.1097/ALN.0000000000000807Scopus ID
2-s2.0-84942056683 (requires institutional sign-in at Scopus site) 69 CitationsAbstract
BACKGROUND: The role of microRNA-21 in isoflurane-induced cardioprotection is unknown. The authors addressed this issue by using microRNA-21 knockout mice and explored the underlying mechanisms.
METHODS: C57BL/6 and microRNA-21 knockout mice were echocardiographically examined. Mouse hearts underwent 30 min of ischemia followed by 2 h of reperfusion in vivo or ex vivo in the presence or absence of 1.0 minimum alveolar concentration of isoflurane administered before ischemia. Cardiac Akt, endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS) proteins were determined by Western blot analysis. Opening of the mitochondrial permeability transition pore (mPTP) in cardiomyocytes was induced by photoexcitation-generated oxidative stress and detected by rapid dissipation of tetramethylrhodamine ethyl ester fluorescence using a confocal microscope.
RESULTS: Genetic disruption of miR-21 gene did not alter phenotype of the left ventricle, baseline cardiac function, area at risk, and the ratios of phosphorylated-Akt/Akt, phosphorylated-eNOS/eNOS, and phosphorylated-nNOS/nNOS. Isoflurane decreased infarct size from 54 ± 10% in control to 36 ± 10% (P < 0.05, n = 8 mice per group), improved cardiac function after reperfusion, and increased the ratios of phosphorylated-Akt/AKT, phosphorylated-eNOS/eNOS, and phosphorylated-nNOS/nNOS in C57BL/6 mice subjected to ischemia-reperfusion injury. These beneficial effects of isoflurane were lost in microRNA-21 knockout mice. There were no significant differences in time of the mPTP opening induced by photoexcitation-generated oxidative stress in cardiomyocytes isolated between C57BL/6 and microRNA-21 knockout mice. Isoflurane significantly delayed mPTP opening in cardiomyocytes from C57BL/6 but not from microRNA-21 knockout mice.
CONCLUSIONS: Isoflurane protects mouse hearts from ischemia-reperfusion injury by a microRNA-21-dependent mechanism. The Akt/NOS/mPTP pathway is involved in the microRNA-21-mediated protective effect of isoflurane.
Author List
Qiao S, Olson JM, Paterson M, Yan Y, Zaja I, Liu Y, Riess ML, Kersten JR, Liang M, Warltier DC, Bosnjak ZJ, Ge ZDAuthor
Jessica Olson PhD Director, Assistant Professor in the Institute for Health and Equity department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCardiotonic Agents
Cells, Cultured
Isoflurane
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
MicroRNAs
Mitochondrial Membrane Transport Proteins
Myocardial Reperfusion Injury
Myocytes, Cardiac
Nitric Oxide Synthase
Organ Culture Techniques
Proto-Oncogene Proteins c-akt
Signal Transduction
