The metabolic syndrome has been defined clinically as a disorder characterized by dyslipidemia, hypertension, central obesity, hyperglycemia and a predisposition to premature atherosclerotic cardiovascular disease and type 2 diabetes. In addition it is associated with microvascular rarefaction and impaired angiogenesis. In both humans and experimental animals the metabolic syndrome is typically accompanied and preceded by insulin resistance, lipid abnormalities and a proinflammatory state. We and others have proposed that these abnormalities could be the result of dysregulation of the fuel-sensing enzyme AMP-activated protein kinase (AMPK). This program will focus on the endothelium, which is generally believed to be the first vascular cell altered during both atherogenesis and impaired angiogenesis. Two major hypotheses will be tested: 1) that the vascular abnormalities associated with the metabolic syndrome are caused in part by dysregulation of AMPK (decreased basal activity or impaired activation) in the endothelial cell as well as peripheral tissues and 2) that such dysregulation is the result of impairment of a SIRT1/LKB1 signaling mechanism that we have demonstrated regulates AMPK activity in various cultured cells and in the liver in vivo (See Project 1). The three projects will individually and collectively characterize the SIRT1/LKB1/AMPK mechanism in cultured vascular endothelial cells and determine the effects of its activation and inhibition on the proatherogenic effects of glucose, FFA and TNF? (Projects 1, 2) and the angiogenic response to ischemia (Project 3). We will also explore the hypothesis that oxidative stress causes post-translational modifications of SIRT1 that can be prevented by AMPK activation (Projects 2, 1). Finally, we will develop transgenic mice with an endothelial cell specific deletion of SIRT1 or LKB1 (Core B). We will then assess the effect of these deletions on muscle capillarity (Projects 3 and 1) and atherogenic changes in the aorta (Project 2) in control mice and mice fed a high-fat/high sucrose diet. In addition, we will assess the anti-atherogenic and pro-angiogenic effects of exercise in these mice (Projects 1-3). A program project grant is requested because of the interactive nature of the research and the use of experimental models that are most effectively studied by multiple investigators. The metabolic syndrome affects over 60,000,000 people in the U.S. over the age of 20 and is a major public health problem. The proposed studies should both yield novel insights into the biological bases for the premature atherosclerosis and impaired angiogenesis associated with this entity and suggest new therapeutic targets for their prevention.
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