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.
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