This proposal explores the expression and function of the mineralocorticoid receptor (MR) in vascular biology. Aldosterone is synthesized by both the adrenal cortex and by vascular cells following angiotensin-2 (All) stimulation or vascular injury. Aldosterone is now recognized to directly cause endothelial damage and VSMC proliferation. Aldosterone, like all steroid hormones, binds to a ligand-activated transcription factor that is a member of the nuclear hormone receptor superfamily. Clinical and animal studies both show that aldosterone directly effects blood vessels. Angiotensin converting enzyme (ACE) inhibitors, a mainstay of cardiovascular therapy, inhibit All and aldosterone production. In large heart failure trials, ACE inhibitors consistently reduce both LV remodeling and, surprisingly, recurrent ischemic events. Furthermore, MR antagonists decrease myocardial infarctions and overall mortality in coronary artery disease and heart failure patients independent of any renal effects. Abundant data show that aldosterone is both a stimulant of endothelin (ET-1) production by vascular cells and a potent smooth muscle cell (VSMC) mitogen. Based on these and related data, we propose to test the hypothesis that aldosterone activates functional mineralocorticoid receptors in VSMC, increases production of endothelin, and promotes VSMC proliferation. The applicant's new preliminary data demonstrate expression of functional MR in human VSMC.
Three Specific Aims are proposed to investigate the mechanism of aldosterone action on VSMCs (SA1); direct, MR-dependent effects of aldosterone on VSMC ET-1 gene expression (SA2); and the role of MR and endothelin in aldosterone mediated VSMC proliferation (SA3). The proposal uses state-of-the-art molecular and cellular approaches and specialized resources developed by the Sponsor's laboratory. The candidate is a M.D.-Ph.D with extensive training in the nuclear hormone receptor field, now completing subspecialty training in cardiovascular medicine. The sponsor is an established cardiovascular physician-scientist with a major laboratory program in the molecular biology of steroid hormone receptor actions in the cardiovascular system. The proposed training is expected to provide training in vascular biology and establish the independent career of an evolving cardiovascular physician-scientist. The studies described will contribute to understanding of the molecular mechanism of aldosterone actions on the vasculature, and the beneficial effects of ACE inhibitors on ischemic cardiovascular events. The studies may also lead to new targets for the therapy of vascular diseases.
