Cardiac Myocyte–Specific Expression of Inducible Nitric Oxide Synthase Protects Against Ischemia/Reperfusion Injury by Preventing Mitochondrial Permeability Transition
Open accessAbstract
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 (α-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 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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Many studies show that BH4 levels correlate with eNOS activity.
“Many studies have shown that BH4 levels correlate with eNOS activity (796, 1006).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [1006]
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- [36]Javadov SA Clarke S Das M Griffiths EJ Lim KH Halestrap AP Ischaemic preconditioning inhibits opening of mitochondrial permeability transition pores in the reperfused rat heart J Physiol 2003 549 513 524 12692185 PMC2342939
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- Authors
- West, M. B., Rokosh, G., Obal, D., Velayutham, M., Xuan, Y.-T., Hill, B. G., Keith, R. J., Schrader, J., Guo, Y., Conklin, D. J., Prabhu, S. D., Zweier, J. L., Bolli, R., & Bhatnagar, A.
- Affiliations
- University of Louisville (US)
- 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...
- ORCID
- Venue
- Circulation
- Published
- 2008-11-04
- Volume
- 118
- Issue
- 19
- Pages
- 1970-1978
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC2763350
- OpenAlex
- W2003937760
- Cited by
- 121
- References
- 38
- Citations by year
- 2025: 5 · 2023: 3 · 2022: 1 · 2021: 3 · 2020: 1 · 2019: 3 · 2018: 10 · 2017: 9 · 2016: 5 · 2015: 9 · 2014: 9 · 2013: 5 · 2012: 13
- FWCI
- 10.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL-89380, R01HL072410, R01HL063744, P01HL078825, HL 59378, R01HL089380, R01HL070897, HL 65608, P01HL065608, R01HL059378, HL 63744, R37HL055757, HL 78825, HL 55757, HL-76794, R01HL055757, HL-68088, R01HL055477, HL70897, R01HL065660, HL65660, HL55477, R01HL076794, R01HL068088)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- inducible nitric oxide synthase, ischemia-reperfusion injury, mitochondrial permeability transition, cardioprotection, nitric oxide, cytochrome c release, NAD+ depletion, oxygen free radicals, mitochondrial swelling, transgenic mice, alpha-myosin heavy chain promoter, cyclosporine, atractyloside, myocardial infarct size
- MeSH terms
- Animals, Electron Spin Resonance Spectroscopy, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Perfusion, Polyamines, Spermine, Myocardial Reperfusion Injury, Gene Expression Regulation, Enzymologic, Reactive Oxygen Species, Ischemic Preconditioning, Myocardial, Nitric Oxide Donors, Myocytes, Cardiac, Mice, Nitric Oxide Synthase Type II
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