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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059652-03
Application #
6056482
Study Section
Special Emphasis Panel (ZHL1-CSR-N (S1))
Project Start
1997-09-30
Project End
2000-07-31
Budget Start
1999-09-01
Budget End
2000-07-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
Ballinger, Scott W; Patterson, Cam; Knight-Lozano, Cynthia A et al. (2002) Mitochondrial integrity and function in atherogenesis. Circulation 106:544-9
Barry-Lane, P A; Patterson, C; van der Merwe, M et al. (2001) p47phox is required for atherosclerotic lesion progression in ApoE(-/-) mice. J Clin Invest 108:1513-22
Moon, S K; Thompson, L J; Madamanchi, N et al. (2001) Aging, oxidative responses, and proliferative capacity in cultured mouse aortic smooth muscle cells. Am J Physiol Heart Circ Physiol 280:H2779-88
Patterson, C; Stouffer, G A; Madamanchi, N et al. (2001) New tricks for old dogs: nonthrombotic effects of thrombin in vessel wall biology. Circ Res 88:987-97
Ballinger, S W; Patterson, C; Yan, C N et al. (2000) Hydrogen peroxide- and peroxynitrite-induced mitochondrial DNA damage and dysfunction in vascular endothelial and smooth muscle cells. Circ Res 86:960-6