title: Nitric oxide donors protect murine myocardium against infarction via modulation of mitochondrial permeability transition.
abstract: Mitochondrial permeability transition (MPT) pores have recently been implicated as a potential mediator of myocardial ischemic injury. Nitric oxide (NO) donors induce a powerful late phase of cardioprotection against ischemia-reperfusion injury; however, the cellular mechanisms involved are poorly understood. The role of MPT pores as a target of cardioprotective signaling pathways activated by NO has never been explored in detail. Thus mice were administered the NO donor diethylenetriamine (DETA)/NO (4 doses of 0.1 mg/kg i.v. each) 24 h before 30 min of coronary artery occlusion followed by 24 h of reperfusion. Infarct size was significantly reduced in DETA/NO-treated mice (30 +/- 2% of risk region in treated mice vs. 50 +/- 2% in control mice; P < 0.05), which demonstrates powerful cardioprotection. To examine the role of MPT pores, mice were administered atractyloside (Atr; 25 mg/kg i.v.), which induces adenine nucleotide translocase-dependent MPT, 20 min before ischemia. Atr blocked the infarct-sparing effects of DETA/NO (infarct size, 58 +/- 1 vs. 30 +/- 2% of risk region in DETA/NO; P < 0.05), whereas Atr alone had no effect. Mitochondria isolated from DETA/NO-treated mice exhibited increased resistance to Ca(2+)-induced swelling by 20 micromol/l CaCl(2) or by the higher concentration of 200 micromol/l, which suggests that cardioprotection involves decreased propensity for MPT. Preincubation of mitochondria from control hearts with 30 nmol/l of the pore inhibitor cyclosporin A prevented swelling by 200 micromol/l CaCl(2), thereby confirming that Ca(2+) induces mitochondrial swelling via MPT. In accordance with the effects on infarct size, administration of Atr to the mice significantly abrogated DETA/NO-induced protection against Ca(2+)-induced mitochondrial swelling. These phenotypic alterations were associated with an increase in the antiapoptotic protein Bcl-2, which suggests that the underlying mechanisms may involve inhibition of cell death by Bcl-2. These data suggest that a critical process during NO donor-induced cardioprotection is to prevent MPT pore opening potentially via targeting of the adenine nucleotide translocator.
authors.affiliation: Department of Physiology, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.
authors.forename: Guangwu
authors.initials: G
authors.lastname: Wang
authors.forename: David A
authors.initials: DA
authors.lastname: Liem
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Vondriska
authors.forename: Henry M
authors.initials: HM
authors.lastname: Honda
authors.forename: Paavo
authors.initials: P
authors.lastname: Korge
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Pantaleon
authors.forename: Xin
authors.initials: X
authors.lastname: Qiao
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.forename: James N
authors.initials: JN
authors.lastname: Weiss
authors.forename: Peipei
authors.initials: P
authors.lastname: Ping
mesh_terms: D000818:Animals; D001278:Atractyloside / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008933:Mitochondrial Swelling / Q000187:drug effects; D009203:Myocardial Infarction / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D011073:Polyamines / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D011073:Polyamines; D019253:Proto-Oncogene Proteins c-bcl-2; C005391:diethylenetriamine; D001278:Atractyloside; D009569:Nitric Oxide; D002118:Calcium