Hydrogen peroxide- and peroxynitrite-induced mitochondrial DNA damage and dysfunction in vascular endothelial and smooth muscle cells.
The mechanisms by which reactive species (RS) participate in the development of atherosclerosis remain incompletely understood. The present study was designed to test the hypothesis that RS produced in the vascular environment cause mitochondrial damage and dysfunction in vitro and, thus, may contribute to the initiating events of atherogenesis. DNA damage was assessed in vascular cells exposed to superoxide, hydrogen peroxide, nitric oxide, and peroxynitrite. In both vascular endothelial and smooth muscle cells, the mitochondrial DNA (mtDNA) was preferentially damaged relative to the transcriptionally inactive nuclear beta-globin gene. Similarly, a dose-dependent decrease in mtDNA-encoded mRNA transcripts was associated with RS treatment. Mitochondrial protein synthesis was also inhibited in a dose-dependent manner by ONOO(-), resulting in decreased cellular ATP levels and mitochondrial redox function. Overall, endothelial cells were more sensitive to RS-mediated damage than were smooth muscle cells. Together, these data link RS-mediated mtDNA damage, altered gene expression, and mitochondrial dysfunction in cell culture and reveal how RS may mediate vascular cell dysfunction in the setting of atherogenesis.
Ballinger
S W
SW
Sealy Center for Molecular Cardiology, Division of Cardiology, Sealy Center for Molecular Science, University of Texas Medical Branch, Galveston, Texas, USA.
Patterson
C
C
Yan
C N
CN
Doan
R
R
Burow
D L
DL
Young
C G
CG
Yakes
F M
FM
Van Houten
B
B
Ballinger
C A
CA
Freeman
B A
BA
Runge
M S
MS
D002478:Cells, Cultured; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000187:drug effects* / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D009566:Nitrates / Q000494:pharmacology*; D016877:Oxidants / Q000494:pharmacology*; D014176:Protein Biosynthesis
D004272:DNA, Mitochondrial; D009566:Nitrates; D016877:Oxidants; C039642:peroxynitric acid; D006861:Hydrogen Peroxide