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: Guangwu Wang, David A Liem, Thomas M Vondriska, Henry M Honda, Paavo Korge, Dawn M Pantaleon, Xin Qiao, Yibin Wang, James N Weiss, Peipei Ping
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 288 Issue 3 Pg. H1290-5 (Mar 2005) ISSN: 0363-6135 [Print] United States
• PMID: 15528225 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cardiotonic Agents
• Enzyme Inhibitors
• Nitric Oxide Donors
• Polyamines
• Proto-Oncogene Proteins c-bcl-2
• diethylenetriamine
• Atractyloside
• Nitric Oxide
• Calcium

Topics

• Animals
• Atractyloside (pharmacology)
• Calcium (pharmacology)
• Cardiotonic Agents (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Male
• Mice
• Mice, Inbred ICR
• Mitochondria (drug effects, metabolism)
• Mitochondrial Swelling (drug effects)
• Myocardial Infarction (metabolism, prevention & control)
• Myocardium (metabolism, pathology)
• Nitric Oxide (metabolism)
• Nitric Oxide Donors (pharmacology)
• Polyamines (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Up-Regulation (drug effects)