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The opposite roles of nNOS in cardiac ischemia-reperfusion-induced injury and in ischemia preconditioning-induced cardioprotection in mice.

Abstract
The role of neuronal nitric oxide synthase (nNOS) in cardiac ischemia-reperfusion (IR) and ischemia preconditioning (IP) is still controversial. Here, we focused on the possible roles of nNOS in cardiac IR and IP. Wild type C57BL/6 (WT) mice were subjected to coronary artery occlusion for 30 min followed by 24-h reperfusion (IR). Cardiac injury (infarct size and apoptotic cell number) was increased, associated with elevation of oxidative stress (lipid peroxidation) and nitrative stress (nitrotyrosine formation). A potent nNOS inhibitor, L-VNIO, and a superoxide dismutase mimetic and peroxynitrite scavenger, MnTBAP, significantly reduced IR-induced increases of oxidative/nitrative stress and cardiac injury. IR-induced cardiac injury in nNOS(-/-) (KO) mice was significantly lower than that in WT mice. MnTBAP markedly reduced IR-induced cardiac injury by suppression of oxidative/nitrative stress in KO mice. Cardiac IP was performed by three cycles of 5-min IR before 30-min ischemia followed by 24-h reperfusion. IP attenuated IR-induced cardiac injury in WT mice associated with reductions of oxidative/nitrative stress. IP-induced reduction of cardiac injury and oxidative/nitrative stress were eliminated by pretreatment with L-VNIO. In contrast with WT mice, IP had no protective effects in nNOS KO mice. In conclusion, nNOS played a dual role during cardiac IR and IP; nNOS exacerbated IR-induced injury by increasing oxidative/nitrative stress and contributed to IP-induced protection by inhibition of oxidative/nitrative stress.
AuthorsXiao-Mei Lu, Guo-Xing Zhang, Yan-Qiu Yu, Shoji Kimura, Akira Nishiyama, Hiroko Matsuyoshi, Juichiro Shimizu, Miyako Takaki
JournalThe journal of physiological sciences : JPS (J Physiol Sci) Vol. 59 Issue 4 Pg. 253-62 (Jul 2009) ISSN: 1880-6562 [Electronic] Japan
PMID19340535 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Enzyme Inhibitors
  • Free Radical Scavengers
  • Metalloporphyrins
  • N(5)-(1-imino-3-butenyl)ornithine
  • Reactive Nitrogen Species
  • Thiobarbituric Acid Reactive Substances
  • manganese(III)-tetrakis(4-benzoic acid)porphyrin
  • 3-nitrotyrosine
  • Tyrosine
  • Ornithine
  • Nitric Oxide Synthase Type I
  • Nos1 protein, mouse
Topics
  • Animals
  • Apoptosis (drug effects)
  • Enzyme Inhibitors (pharmacology)
  • Free Radical Scavengers (pharmacology)
  • Ischemic Preconditioning, Myocardial
  • Lipid Peroxidation (drug effects)
  • Metalloporphyrins (pharmacology)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardial Infarction (metabolism, pathology)
  • Myocardial Reperfusion Injury (enzymology, etiology, pathology, prevention & control)
  • Myocardium (metabolism, pathology)
  • Nitric Oxide Synthase Type I (antagonists & inhibitors, deficiency, genetics, physiology)
  • Ornithine (analogs & derivatives, pharmacology)
  • Oxidative Stress (drug effects)
  • Reactive Nitrogen Species (metabolism)
  • Thiobarbituric Acid Reactive Substances (metabolism)
  • Tyrosine (analogs & derivatives, metabolism)

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