The renin-angiotensin aldosterone system (RAAS) plays an integral role in cardiovascularhomeostasis through its effects on vascular tone and volume, and pharmacological interruption of this system has found widespread clinical application. Independent of the effects of the RAAS on blood pressure, activation of this system accelerates the development of atherosclerosis in experimental models and has been identified as a risk factor for the development of ischemic heart disease in man. Although multiple mechanisms may be responsible for this association, we have focused on the interaction between the RAAS and plasminogen activator inhibitor-1 (PAI-1). The central hypothesis of this proposal is that PAI-1 modulates the inflammatory effects associatedwith activation of the RAAS by influencing macrophage biology and migratory capacity. A multifaceted research strategy employing murine models of atherosclerosis and obesity are proposed to test this hypothesis.
The specific aims of this proposal are the following: 1) To test the hypothesis that PAI-1 modulates the development of coronary atherosclerosis in response to Ang II; 2) To characterize the mechanistic interaction between Ang II and PAI-1 on inflammatory amplification in obesity; and 3) To define and characterize the mechanism of the anti-inflammatory effects of PAI-1 in atherosclerosis and obesity. It is anticipated that these studies will generate important new information regarding the""""""""anti-inflammatory"""""""" role of PAI-1 in obesity and atherosclerosis. Furthermore, this project may contribute to our understanding of the regulation of two systems that play vital roles in cardiovascular homeostasis, and thus may improve our ability to prevent and treat atherothrombotic cardiovascular disease.
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