Cardiac Myocyte–Specific Expression of Inducible Nitric Oxide Synthase Protects Against Ischemia/Reperfusion Injury by Preventing Mitochondrial Permeability Transition

作者：Matthew West, Gregg D. Rokosh, Detlef Obal, Murugesan Velayutham, Yu‐Ting Xuan, Bradford G. Hill, Rachel J. Keith, Jürgen Schrader, Yiru Guo, Daniel J. Conklin, Sumanth D. Prabhu, Jay Louis Zweier, Roberto Bolli, Aruni Bhatnagar · 发表于：Circulation · 年份：2008 · DOI：10.1161/circulationaha.108.791533 · 被引用次数：122 · 研究领域：Cardiac Ischemia and Reperfusion、Nitric Oxide and Endothelin Effects、Cardiovascular Function and Risk Factors

BACKGROUND: Inducible nitric oxide synthase (iNOS) is an obligatory mediator of the late phase of ischemic preconditioning, but the mechanisms of its cardioprotective actions are unknown. In addition, it remains unclear whether sustained elevation of iNOS in myocytes provides chronic protection against ischemia/reperfusion injury. METHODS AND RESULTS: Constitutive overexpression of iNOS in transgenic mice (alpha-myosin heavy chain promoter) did not induce contractile dysfunction and did not affect mitochondrial respiration or biogenesis, but it profoundly decreased infarct size in mice subjected to 30 minutes of coronary occlusion and 24 hours of reperfusion. In comparison with wild-type hearts, isolated iNOS-transgenic hearts subjected to ischemia for 30 minutes followed by 40 minutes of reperfusion displayed better contractile recovery, smaller infarct size, and less mitochondrial entrapment of 2-deoxy-[(3)H]-glucose. Reperfusion-induced loss of NAD(+) and mitochondrial release of cytochrome c were attenuated in iNOS-transgenic hearts, indicating reduced mitochondrial permeability transition. The NO donor NOC-22 prevented permeability transition in isolated mitochondria, and mitochondrial permeability transition-induced NAD(+) loss was decreased in wild-type but not iNOS-null mice treated with the NO donor diethylene triamine/NO 24 hours before ischemia and reperfusion ex vivo. iNOS-mediated cardioprotection was not abolished by atractyloside. Reperfusion-induced production...