Superoxide and other reactive oxygen species play a pivotal role in a variety of vascular diseases. This project continues the initial theme of the project, related to effects of superoxide on endothelial function in atherosclerosis and after regression, with a new emphasis on thrombotic and antithrombotic mechanisms. The goal of Aim 1 is to study effects of an important antioxidant enzyme, extracellular superoxide dismutase (ECSOD) and a common human gene variant of that enzyme. The investigators reported that the heparin-binding domain (HBD) of ECSOD is essential for normal functon of ECSOD. A common gene variant in the HBD of ECSOD, R213G, may be an extremely important risk factor for ischemic heart disease. The investigators have made a recombinant adenovirus that expresses ECSOD R213G and propose to examine vascular effects of the gene variant. Studies are proposed to test the hypothesis that ECSOD, but not ECSOD R213G, attenuates inflammation and protects endothelial function after bacterial endotoxin. The goal of Aim 2 is to examine effects of atherosclerosis and ECSOD on endothelial antithrombotic func-tion and susceptibility to thrombosis in mice. Studies are proposed to test the hypothesis that accelerated thrombosis in atherosclerotic mice is caused by oxidative stress and decreased bioavailability of endothe-lium-derived nitric oxide, with decreased activation of anticoagulant protein C. Effects of atherosclerosis on endothelial antithrombotic function also will be examined in a novel strain of knock-in mice that express human thrombomodulin and have diminished capacity to activate anticoagulant protein C. The goal of Aim 3 is to examine effects of regression of atherosclerosis on endothelial vasomotor and anti-thrombotic function in mice. In """"""""Reversa"""""""" mice, hypercholesterolemia can be reversed with a genetic switch. After Cre induction, the gene for microsomal triglyceride transfer protein is virtually eliminated, so that plasma cholesterol in LDLr-/- apoB 100/100 mice is reduced to normal levels. Studies are proposed to test the hypothesis that regression of atherosclerosis in Reversa mice improves endothelial vasomotor function in aorta and coronary arteries, reduces superoxide in blood vessels and aortic valve, and reverses the enhanced susceptibility to thrombosis. The long-term goal of Project 3 is to clarify fundamental mechanisms by which superoxide and antioxidant enzymes modulate endothelial vasomotor and antithrombotic function.
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