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1 Department of Pharmacology and Center for Lunug Biology, University of South Alabama College of Medicine, USA
2 Department of Cell Biology and Neurosciencen, University of South Alabama College of Medicine, USA
3 Department of Pharmacology and Center for Lunug Biology, University of South Alabama College of Medicine, USA; Department of Cell Biology and Neurosciencen, University of South Alabama College of Medicine, USA
* To whom correspondence should be addressed. E-mail: mgillesp{at}jaguar1.usouthal.edu.
Oxidant-induced death and dysfunction of pulmonary vascular cells play important roles in the evolution of acute lung injury. In pulmonary artery endothelial cells (PAECs), oxidant-mediated damage to mitochondrial (mt) DNA seems to be critical in initiating cytotoxicity inasmuch as overexpression of the mitochondrially-targeted, human DNA repair enzyme, hOgg1, prevents both mtDNA damage and cell death (Amer. J. Physiol: Lung Cell Molec. Physiol. 283: L205-10, 2002). The mechanism by which mtDNA damage leads to PAEC death is unknown, and the present study tested the specific hypothesis that enhanced mtDNA repair suppresses PAEC mitochondrial dysfunction and apoptosis evoked by xanthine oxidase (XO). PAECs transfected with either an adenoviral vector encoding hOgg1 linked to a mitochondrial targeting sequence or with empty vector were challenged with ascending doses of XO plus hypoxanthine. Quantitative Southern blot analyses revealed that, as expected, hOgg1 over-expression suppressed XOinduced mtDNA damage. Mitochondrial over-expression of hOgg1 also suppressed the XO-mediated loss of mitochondrial membrane potential. Importantly, hOgg1 over-expression attenuated XO-induced apoptosis as detected by suppression of caspase 3 activation, by reduced DNA fragmentation, and by a blunted appearance of condensed, fragmented nuclei. These observations suggest that mtDNA damage serves as a trigger for mitochondrial dysfunction and apoptosis in XO-treated PAECs.
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