Aldosterone activates mineralocorticoid receptors (MR) in the kidney to regulate sodium handling and blood pressure (BP). Elevated aldosterone is common in growing populations including resistant hypertension, obesity, and heart failure and predicts the risk of myocardial infarction (MI), stroke and death in these patients. MR antagonists prevent these outcomes out of proportion to BP changes leading to the overarching hypothesis of this program: that vascular MR contributes directly to vascular function and cardiovascular disease (CVD) and that identification of the genes and pathways controlled by vascular MR will identify novel mechanisms and therapeutic targets for CVD. We showed that functional MRs exists in human vascular smooth muscle cells (SMC) and endothelial cells (EC). In the first 5 years we focused on SMC-MR and our discoveries, including a novel mechanism for vascular remodeling and a direct role for SMC-MR in BP regulation with aging, have dramatically changed our paradigm of MR biology and mechanisms of CVD. In the next 4 years, we propose to explore the controversial role of EC- MR in CVD. For this purpose, we generated an innovative mouse model with MR specifically deleted from ECs (and not leukocytes) and found that EC-MR deletion prevents obesity- and hyperlipidemia- induced endothelial dysfunction. We propose to use this EC-MR-KO mouse to test the novel hypothesis that EC-MR contributes to the development of endothelial dysfunction, vascular inflammation, and atherosclerosis progression specifically in the presence of cardiac risk factors such as obesity, high BP, and hyperlipidemia. We propose 3 aims: 1) Determining the role of EC-MR in transmitting cardiac risk factors into endothelial dysfunction using mesenteric vessel wire myography from EC-MR-KO and MR- intact mice exposed to cardiac risk factors; 2) Exploring the mechanism by which EC-MR enhances vascular inflammation. Using in vitro parallel plate flow chamber assays, we found that EC-MR enhances T cell adhesion and migration through ECs and we propose to examine the mechanisms both in vitro and also in vivo using flow cytometry and intravital microscopy; and 3) Examining the role of EC-MR in atherosclerosis using EC-MR-KO mice crossed with atherosclerosis-prone ApoE-KO mice. The proposed studies use innovative mouse models to advance our understanding of the mechanism by which common risk factors lead to CVD. Completion of the aims will provide a mechanistic explanation for the enhanced risk of cardiovascular ischemia in growing populations with high aldosterone (heart failure, obesity, resistant HTN, low sodium diet) and for the vascular protective effects of MR antagonists. Furthermore, these studies are expected to identify novel treatment targets to prevent cardiovascular ischemia in these rapidly growing and high risk populations.
Despite recent advances in our understanding of the pathophysiology of atherosclerosis, heart attack and stroke, remain the leading causes of death in the developed world. Clinical studies demonstrate that drugs that prevent the blood pressure-regulating hormone aldosterone from activating the mineralocorticoid receptor prevent heart attacks and strokes by unknown mechanisms. The overall goal of this proposal is to identify the genes and pathways regulated by mineralocorticoid receptors in the blood vessel and to explore the role of these mechanisms in promoting vascular disease in order to identify new therapeutic targets to more effectively prevent and treat heart attacks and strokes.
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