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(Circulation. 2008;118:1970-1978.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

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

Matthew B. West, PhD^*; Gregg Rokosh, PhD^*; Detlef Obal, MD; Murugesan Velayutham, PhD; Yu-Ting Xuan, PhD; Bradford G. Hill, PhD; Rachel J. Keith, MS; Jürgen Schrader, MD; Yiru Guo, MD; Daniel J. Conklin, PhD; Sumanth D. Prabhu, MD; Jay L. Zweier, MD; Roberto Bolli, MD; Aruni Bhatnagar, PhD

From the Institute of Molecular Cardiology (M.B.W., G.R., Y.-T.X., B.G.H., R.J.K., Y.G., D.J.C., S.D.P., R.B., A.B.), Department of Biochemistry and Molecular Biology (M.B.W., B.G.H.), VA Medical Center (S.D.P.), and Department of Anesthesiology and Perioperative Medicine (D.O.), University of Louisville, Louisville, Ky; Department of Cardiovascular Physiology (J.S.) and Department of Anesthesiology (D.O.), University of Düsseldorf, Düsseldorf, Germany; and Center for Biomedical EPR Spectroscopy and Imaging, Davis Heart and Lung Research Institute, and Division of Cardiovascular Medicine, Department of Internal Medicine, Ohio State University College of Medicine, Columbus (M.V., J.L.Z.).

Correspondence to Aruni Bhatnagar, PhD, Division of Cardiology, Department of Medicine, Delia Baxter Bldg, 580 S Preston St, Room 421F, University of Louisville, Louisville, KY 40202. E-mail aruni{at}louisville.edu

Received October 10, 2007; accepted July 7, 2008.

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 (-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-[³H]-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 of oxygen-derived free radicals (measured by electron paramagnetic resonance spectroscopy) was attenuated in iNOS-transgenic hearts and was increased in wild-type hearts treated with the mitochondrial permeability transition inhibitor cyclosporin A.

Conclusions— Cardiomyocyte-restricted expression of iNOS provides sustained cardioprotection. This cardioprotection is associated with a decrease in reperfusion-induced oxygen radicals and inhibition of mitochondrial swelling and permeability transition.

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