Background-Coronary atherosclerotic disease remains the leading cause of death in the Western world. Although the exact sequence of events in this process is controversial, reactive oxygen and nitrogen species (RS) likely play an important role in vascular cell dysfunction and atherogenesis. Oxidative damage to the mitochondrial genome with resultant mitochondrial dysfunction is an important consequence of increased intracellular RS. Methods and Results-We examined the contribution of mitochondrial oxidant generation and DNA damage to the progression of atherosclerotic lesions in human arterial specimens and atherosclerosis-prone mice. Mitochondrial DNA damage not only correlated with the extent of atherosclerosis in human specimens and aortas from apolipoprotein E Ϫ/Ϫ mice but also preceded atherogenesis in young apolipoprotein E Ϫ/Ϫ mice. Apolipoprotein E Ϫ/Ϫ mice deficient in manganese superoxide dismutase, a mitochondrial antioxidant enzyme, exhibited early increases in mitochondrial DNA damage and a phenotype of accelerated atherogenesis at arterial branch points. Key Words: atherosclerosis Ⅲ muscle, smooth Ⅲ antioxidants R eactive species (RS) define a collective grouping of reactive oxygen and nitrogen species that can alter the biological functions of essential molecules such as lipids, proteins, and DNA. Numerous studies have linked excess RS generation with vascular lesion formation and functional defects. [1][2][3] This association has been reported for various RS models and species. 4 -6 A role for RS in atherogenesis is supported by epidemiological evidence of links between common risk factors for coronary artery disease and increased levels of RS. [7][8][9] Among the extensively studied intracellular systems capable of generating RS in vascular cells are the NADH/NADPH oxidase, xanthine oxidase, lipoxygenase, and cyclooxygenase systems. 6,10 -12 Mitochondria are biologically important sources and targets for RS. 13,14 However, their role as mediators of oxidative disease processes such as atherogenesis has not been examined. We recently reported that exposure of vascular cells to RS in vitro results in preferential mitochondrial DNA (mtDNA) damage and dysfunction and that mtDNA damage is a very sensitive marker for RS-mediated cellular effects. 15 In addition to the potential role of mtDNA damage as a marker of ambient oxidative stress, oxidative damage to the mitochondrion can lead to decreased oxidative energetic capacity (via impaired oxidative phosphorylation) and increased generation of intracellular RS. 15-17 Thus, we hypothesized that mitochondrial dysfunction accentuates atherosclerosis by modulating the phenotype of vascular cells and that measurements of mtDNA damage reflect RS-mediated atherosclerosis risk. Conclusions-MitochondrialUsing human aortic specimens and a murine model of early atherogenesis (the apolipoprotein E null, apoE Ϫ/Ϫ ), we examined the correlation between mtDNA damage and atherogenesis and sought to determine whether mtDNA damage is a cause or an effect in this pr...

Background-A shared feature among cardiovascular disease risk factors is increased oxidative stress. Because mitochondria are susceptible to damage mediated by oxidative stress, we hypothesized that risk factors (secondhand smoke and hypercholesterolemia) are associated with increased mitochondrial damage in cardiovascular tissues. Methods and Results-Atherosclerotic lesion formation, mitochondrial DNA damage, protein nitration, and specific activities of mitochondrial proteins in cardiovascular tissues from age-matched C57 and apoE Ϫ/Ϫ mice exposed to filtered air or secondhand smoke were quantified. Both secondhand smoke and hypercholesterolemia were associated with significantly increased mitochondrial DNA damage and protein nitration. Tobacco smoke exposure also resulted in significantly decreased specific activities of mitochondrial enzymes. The combination of secondhand smoke and hypercholesterolemia resulted in increased atherosclerotic lesion formation and even greater levels of mitochondrial damage. Conclusions-These