The renin-angiotensin system (RAS) plays an integral role in cardiovascular homeostasis through its effects on vascular tone and volume, and pharmacologic interruption of this system has found widespread clinical application. Independent of effects of the RAS on blood pressure, activation of this system has been identified as a risk factor for the development of acute myocardial infarction (MI). It is hypothesized that activation of the RAS exerts a deleterious influence on fibrinolytic balance, and as such, reduces the activity of one of the major endogenous defense mechanisms against intravascular thrombosis. Vascular fibrinolytic balance is, to a large part, determined by the Competing effects of plasminogen activators and plasminogen activator inhibitor-1 (PAI-1), both of which are synthesized and secreted by the endothelium. This proposal is based on recent studies that establish the presence of a critical physiological relationship between the RAS and the fibrinolytic system. Preliminary data presented herein demonstrate that angiotensin: a) induces dose-dependent increases in endothelial PAI-1 production (mRNA and protein) in vitro; and b) selectively stimulates PAI- 1 secretion in vivo in humans. Moreover, recent studies performed in this laboratory confirm published reports that a novel form of receptor for angiotensin is present on endothelial cells, and provide the initial evidence that the hexapeptide angiotensin II (3-8), termed angiotensin IV (Ang IV) is the form of angiotensin that is responsible for the induction of endothelial PAI-1 production. These findings are particularly germane to our understanding of the mechanisms responsible for the newly- recognized anti-ischemic effects of ACE inhibitors, since elevated levels of PAI-1 constitute a risk factor for MI. This proposal is designed to examine endothelial cells as a target organ for angiotensin and to investigate the coordinated regulation of the RAS an endothelial fibrinolysis.
The specific aims of this proposal are the following: 1. To examine the effects of Ang IV on endothelial PAI-1 production and to characterize its mechanism of action; 2. To characterize the biochemical and molecular properties of the endothelial angiotensin receptor; and 3. To characterize the mechanisms through which ACE inhibitors enhance endothelial production of plasminogen activators. It is anticipated that these studies will generate critical new information regarding the interaction of the RAS, the vascular endothelium, and fibrinolysis. 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 ischemic cardiovascular disease.
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