Reactive oxygen species (ROS) have been suggested to play a role in the pathogenesis of atherosclerotic lesions. Mitochondria generate ROS during oxidative phosphorylation (OXPHOS). Because the mitochondrial DNA lacks protective histone and non-histone proteins, lacks efficient DNA repair systems, is in immediate proximity to OXPHOS, and is associated with the inner membrane (matrix side), it is susceptible to lipophilic substances and mitochondrial generated ROS. Consequently, the mtDNA should be sensitive to ROS mediated damage. MtDNA damage to the endothelial cell will result in decreased OXPHOS function, resulting in greater ROS production, continuing the cycle of mitochondrial function and damage. These effects will ultimately result in endothelial cell dysfunction, an initiating step in atherogenesis. To test the hypothesis that mitochondrial dysfunction and ROS generation are initiators of atherosclerosis, the applicant will address four Specific Aims: 1) To define the independent effects of atherosclerosis and oxidative stress on mtDNA damage, mutagenesis and OXPHOS dysfunction in vivo; 2) To determine whether mitochondrial damage accelerates the development of atherosclerosis in genetically altered mice in vivo; 3) To quantify mtDNA damage and repair in human smooth muscle, endothelial, and monocyte cells exposed to atherogenic stimuli and oxidative stress in vitro; 4) To measure mitochondrial protein synthesis and antioxidant (MnSOD, NOS) expression in human smooth muscle, endothelial, and monocyte cells exposed to ROS in vitro; and 5) To measure mtDNA damage and mutation in both healthy and atherosclerotic human aortic tissue in vivo.
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