Published online before print September 2, 2004, doi: 10.1161/01.RES.0000143898.67182.4c
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© 2004 American Heart Association, Inc.
Integrative Physiology |
Transgenic Expression of Bcl-2 Modulates Energy Metabolism, Prevents Cytosolic Acidification During Ischemia, and Reduces Ischemia/Reperfusion Injury
From the Laboratory of Signal Transduction (K.I., E.M.), National Institutes of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC; Department of Pathology (C.S.), Duke University Medical Center, Durham, NC; and the Department of Medicine (M.D.S.), Molecular and Cellular Biology, and Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Tex.
Correspondence to Elizabeth Murphy, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709. E-mail murphy1{at}niehs.nih.gov
The antiapoptotic protein Bcl-2 is targeted to the mitochondria, but it is uncertain whether Bcl-2 affects only myocyte survival after ischemia, or whether it also affects metabolic functions of mitochondria during ischemia. Hearts from mice overexpressing human Bcl-2 and from their wild-type littermates (WT) were subjected to 24 minutes of global ischemia followed by reperfusion. During ischemia, the decrease in pHi and the initial rate of decline in ATP were significantly reduced in Bcl-2 hearts compared with WT hearts (P<0.05). The reduced acidification during ischemia was dependent on the activity of mitochondrial F1F0-ATPase. In the presence of oligomycin (Oligo), an F1F0-ATPase inhibitor, the decrease in pHi was attenuated in WT hearts, but in Bcl-2 hearts, Oligo had no additional effect on pHi during ischemia. Likewise, addition of Oligo to WT hearts slowed the rate of decline in ATP during ischemia to a level similar to that observed in Bcl-2 hearts, but addition of Oligo had no significant effect on the rate of decline in ATP in Bcl-2 hearts during ischemia. These data are consistent with Bcl-2–mediated inhibition of consumption of glycolytic ATP. Furthermore, mitochondria from Bcl-2 hearts have a reduced rate of consumption of ATP on uncoupler addition. This could be accomplished by limiting ATP entry into the mitochondria through the voltage-dependent anion channel, and/or the adenine nucleotide transporter, or by direct inhibition of the F1F0-ATPase. Immunoprecipitation showed greater interaction between Bcl-2 and voltage-dependent anion channel during ischemia. These data indicate that Bcl-2 modulation of metabolism contributes to cardioprotection.
Key Words: transgenic models • magnetic resonance spectroscopy • mitochondria • reperfusion injury
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