Results from the World Health Organization MONICA Project confirm that coronary artery disease resulting from atherosclerosis is the major determinant of mortality in the Western population. Vascular injury leading to the production of cell activating factors such as thrombin and the ensuing robust vasculoproliferative response is a major contributory mechanism in the production of occlusive coronary lesions. Though many pathways lead to atherogenesis, oxidative stress and oxidative signaling have been demonstrated to provide a common link. In the previous grant period, we focused on the mechanisms by which ROS are produced in the vessel wall, studying the molecular events that occur following interaction of thrombin with its receptors on vascular cells. The goal of this proposal is to examine the relationship between ROS and atherogenesis, with the overall goal of defining the mechanisms by which vascular cells generate ROS and ROS-mediated molecular events that contribute to normal and pathologic vascular formation.
Our specific aims to: 1) determine the thrombin-mediated molecular events that result in NADPH oxidase activation in VSMC, and whether other mediators (such as Angiotensin II and TNF-alpha) utilize common signaling mechanisms; 2) determine the balance between oxidative stress and protective responses in VSMC and their relative roles in atherosclerosis; and 3) identify genetic factors that influence susceptibility to oxidative stress and atherosclerosis. These studies will elucidate common mechanisms in atherosclerosis that regulate intracellular ROS production and vascular cell growth, hopefully leading to the identification of new, highly specific targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057352-06
Application #
6607290
Study Section
Special Emphasis Panel (ZRG1-PTHA (01))
Program Officer
Srinivas, Pothur R
Project Start
1997-08-01
Project End
2006-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
6
Fiscal Year
2003
Total Cost
$327,375
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Zhou, Rui-Hai; Vendrov, Aleksandr E; Tchivilev, Igor et al. (2012) Mitochondrial oxidative stress in aortic stiffening with age: the role of smooth muscle cell function. Arterioscler Thromb Vasc Biol 32:745-55
Madamanchi, Nageswara R; Runge, Marschall S (2010) NADPH oxidases and atherosclerosis: unraveling the details. Am J Physiol Heart Circ Physiol 298:H1-2
Runge, Marschall S; Molnar, Kimberly; Madamanchi, Nageswara R (2010) ""Old"" hearts and arteries: the role of oxidative stress. Trans Am Clin Climatol Assoc 121:52-8; discussion 59-60
Niu, Xi-Lin; Madamanchi, Nageswara R; Vendrov, Aleksandr E et al. (2010) Nox activator 1: a potential target for modulation of vascular reactive oxygen species in atherosclerotic arteries. Circulation 121:549-59
Madamanchi, Nageswara R; Zhou, Rui-Hai; Vendrov, Aleksandr E et al. (2010) Does oxidative DNA damage cause atherosclerosis and metabolic syndrome?: new insights into which came first: the chicken or the egg. Circ Res 107:940-2
Vendrov, Aleksandr E; Madamanchi, Nageswara R; Niu, Xi-Lin et al. (2010) NADPH oxidases regulate CD44 and hyaluronic acid expression in thrombin-treated vascular smooth muscle cells and in atherosclerosis. J Biol Chem 285:26545-57
Monaghan-Benson, Elizabeth; Hartmann, John; Vendrov, Aleksandr E et al. (2010) The role of vascular endothelial growth factor-induced activation of NADPH oxidase in choroidal endothelial cells and choroidal neovascularization. Am J Pathol 177:2091-102
Tchivilev, Igor; Madamanchi, Nageswara R; Vendrov, Aleksandr E et al. (2008) Identification of a protective role for protein phosphatase 1cgamma1 against oxidative stress-induced vascular smooth muscle cell apoptosis. J Biol Chem 283:22193-205
Niu, Xi-Lin; Li, Juxiang; Hakim, Zeenat S et al. (2007) Leukocyte antigen-related deficiency enhances insulin-like growth factor-1 signaling in vascular smooth muscle cells and promotes neointima formation in response to vascular injury. J Biol Chem 282:19808-19
Vendrov, Aleksandr E; Hakim, Zeenat S; Madamanchi, Nageswara R et al. (2007) Atherosclerosis is attenuated by limiting superoxide generation in both macrophages and vessel wall cells. Arterioscler Thromb Vasc Biol 27:2714-21

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