Abstract

Arterial injury and subsequent inflammatory events result from local effects of many potential mediators of atherosclerosis, including oxidized LDL and other reactive oxygen species (ROS), thrombin and other growth factors, and cytokines. These factors evoke acute cellular responses, including activation of intracellular signaling pathways, stimulation of DNA synthesis, and phenotypic modulation of vascular wall cells, ultimately leading to the formation and progression of atherosclerotic lesions. The goals of this project are to examine the relationship between oxidative stress and the action of thrombin, a potent vascular smooth muscle cell (VSMC) growth factor; and to determine the mechanisms that govern gene regulation and cell growth in response to these mediators.
Our specific aims are to: 1) determine the role of thrombin in the generation of oxidants in human aortic SMC and VSMC from genetically altered mice that are deficient in either antioxidant or oxidant-generating mechanisms; 2) determine the mechanism(s) responsible for upregulation of thrombin receptor gene expression, leading to """"""""long-term"""""""" modulation of thrombin's effects in atherosclerotic arteris, focusing on potential nuclear regulatory sequences, including the antioxidant response element [ARE] (present in the thrombin receptor promoter region); 3) characterize the protein tyrosine phosphorylation signals that result from stimulation of vascular cells by thrombin and ROS and determine the key events necessary for mitogenesis in VSMC, focusing on the cytosolic Jak- STAT and Src kinase pathways; and 4) determine the role of protein tyrosine phosphatases in sustained oxidative stress-induce mitogenic signaling events, in particular examining leukocyte comon antigen- related (LAR) phosphatase and S77 (a nvel phosphatase), both of which are highly regulated in response to thrombin and ROS and in atherosclerosis. These studies will provide an improved understanding of the molecular mechanisms of atherosclerosis by elucidating the role of oxidative stress in vascular cell growth.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057352-02
Application #
2750590
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1997-08-01
Project End
2001-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Texas Medical Br Galveston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555

  Publications

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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