application): Activation of the renin-angiotensin system (RAS) has been identified as a risk factor for the development of ischemic heart disease, whereas pharmacological interruption of the RAS with angiotensin converting enzyme (ACE) inhibitors reduces the development of atherosclerosis in experimental animals and has been shown to reduce the incidence of recurrent myocardial infarction in selected populations. Recently, common genetic polymorphisms in several components of the RAS, including the ACE gene, have been linked with increased risk of ischemic cardiovascular disease as well. Although multiple mechanisms may contribute to this association between the RAS and ischemic cardiovascular disease, the investigators have focused on the effects of the RAS on the plasminogen activator system, which serves as one of the major endogenous defense mechanisms against intravascular thrombosis, and plays a critical role in vascular and tissue remodeling as well. Vascular fibrinolytic balance is largely determined by the competing effects of plasminogen activators and plasminogen activator inhibitor-1 (PAI-1), both of which are synthesized in the vascular endothelium. The investigators have shown that Ang II stimulates PAI-1 expression in endothelial cells and, when given in pharmacological doses, can induce increases in plasma PAI-1 in humans. More recent evidence from this laboratory indicates that the induction of PAI-1 expression in endothelial cells is mediated by the Ang II hexapeptide metabolite, Ang IV. In contrast, the investigators have shown that bradykinin induces endothelial production of t-PA in vitro and, when given in pharmacological doses, induces the acute secretion of t-PA in vivo in humans. Thus, ACE is strategically poised to regulate the balance between PAI-1 and t-PA. The purpose of the mechanistic studies presented in this proposal is to test the hypothesis that the endogenous RAS plays a critical role in the regulation of vascular fibrinolytic balance in humans.
In Specific Aim 1, the investigators will examine the interactive effect of genetic polymorphisms within the RAS and fibrinolytic system on plasma fibrinolytic balance. The investigators hypothesize that the ACE deletion allele, which has been associated with the enhanced conversion of Ang I to Ang II, will be associated with increased PAI-1 and that this effect will be greatest in patients who carry the PAI-1 4G allele, a variant previously associated with increased PAI-1 expression.
In Specific Aim 2, the investigators will use pharmacologic tools that inhibit the RAS, including an ACE inhibitor and an AT1 receptor antagonist, to determine the relative contribution of Ang II versus Ang IV to increased PAI-1 expression in vivo, and to determine the role of bradykinin in regulating fibrinolytic balance.
In Specific Aim 3, the investigators will examine the relationship between vascular function and endothelial responsiveness to bradykinin and Ang IV. It is anticipated that these studies will generate critical new information regarding the role to the RAS in regulating vascular fibrinolytic balance and how common functional genetic polymorphisms in these two systems may interact to increase the risk of vascular disease in human hypertension.
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