Regulation of Vascular Inflammation

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DESCRIPTION (provided by applicant): Atherosclerosis is an inflammatory disease. Clinical studies show that elevated serum markers of inflammation predict an increased risk for atherosclerosis. Animal studies show that inflammatory mediators play a role in atherogenesis. Although pro-inflammatory pathways have been shown to increase atherosclerosis, the protective roles of anti-inflammatory pathways are less well studied. We and others have previously shown that nitric oxide (NO) inhibits vascular diseases. ApoE null mice that also lack the endothelial nitric oxide synthase (eNOS, or NOS3) gene have more severe atherosclerosis than ApoE mice that express NOS3. In humans, endothelial dysfunction (characterized by an inability to produce NO) is associated with coronary artery disease (CAD). Thus, NO may protect the vasculature from atherosclerosis. The molecular mechanisms by which NO inhibits atherosclerosis are unknown. However, we and others recently discovered that NOS decreases inflammation in transplant arteriosclerosis. In particular, we found that the inducible nitric oxide synthase (iNOS, or NOS2) inhibits the release of WeibeI-Palade bodies from endothelial cells in donor hearts. Since WeibeI-Palade bodies contain inflammatory and thrombotic mediators, inhibition of WeibeI-Palade body release may explain part of the anti-inflammatory effects of NO in transplant vasculopathy and other inflammatory vascular diseases, including atherosclerosis. We hypothesize that NO derived from NOS inhibits vascular inflammation, in part by inhibiting WeibeI-Palade body exocytosis. We now propose to explore the molecular mechanisms by which NO inhibits WeibeI-Palade body release. Preliminary Data show that NO blocks WeibeI-Palade body release from cultured endothelial cells. We will begin by determining the mechanisms by which WeibeI-Palade bodies are normally released. We will next define the molecules of the exocytosis machinery that are targets of NO. Finally, we will examine the role of reactive oxygen species in regulating WeibeI-Palade body exocytosis. These studies will characterize novel molecular mechanisms by which radicals regulate vascular inflammation.