Journal article
Cardiac Myocyte-Specific Expression of Inducible Nitric Oxide Synthase Protects Against Ischemia/Reperfusion Injury by Preventing Mitochondrial Permeability Transition
Circulation (New York, N.Y.), Vol.118(19), pp.1970-1978
11/04/2008
DOI: 10.1161/CIRCULATIONAHA.108.791533
PMCID: PMC2763350
PMID: 18936326
Abstract
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-[H-3]-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. (Circulation. 2008;44:1970-1978.)
Details
- Title: Subtitle
- Cardiac Myocyte-Specific Expression of Inducible Nitric Oxide Synthase Protects Against Ischemia/Reperfusion Injury by Preventing Mitochondrial Permeability Transition
- Creators
- Matthew B. West - University of LouisvilleGregg Rokosh - University of LouisvilleDetlef Obal - University of LouisvilleMurugesan VelayuthamYu-Ting Xuan - University of LouisvilleBradford G. Hill - University of LouisvilleRachel J. Keith - University of LouisvilleJuergen Schrader - Univ Dusseldorf, Dept Cardiovasc Physiol, Dusseldorf, GermanyYiru Guo - University of LouisvilleDaniel J. Conklin - University of LouisvilleSumanth D. Prabhu - University of LouisvilleJay L. Zweier - University of LouisvilleRoberto Bolli - University of LouisvilleAruni Bhatnagar - University of Louisville
- Resource Type
- Journal article
- Publication Details
- Circulation (New York, N.Y.), Vol.118(19), pp.1970-1978
- Publisher
- Lippincott Williams & Wilkins
- DOI
- 10.1161/CIRCULATIONAHA.108.791533
- PMID
- 18936326
- PMCID
- PMC2763350
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Number of pages
- 9
- Grant note
- HL55477; HL59378; HL78825; HL55757; HL68088; HL76794; HL70897; HL65660; HL89380; HL63744; HL65608 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA American Heart Association R01HL072410 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI)
- Language
- English
- Date published
- 11/04/2008
- Academic Unit
- Anesthesia
- Record Identifier
- 9984696578702771
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