MINERALOCORTICOID RECEPTOR ANTAGONISM CLINICAL EVALUATION IN ATHEROSOCLEROSIS (MAGMA)

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 DESCRIPTION (provided by applicant): We have previously demonstrated that the mineralocorticoid receptor (MR) plays an important role in inflammation in atherosclerosis. Studies from our laboratory suggest a role for monocyte MR activation in monocyte/macrophage inflammation. Further, we have demonstrated a key role for candidate microRNAs (miRNAs) in the regulation of MR (NR3C2) gene expression in monocytes and in the prediction of atherosclerosis. These findings suggest that miRNA expression predicts response to MR blockade in patients. We propose a randomized double blind clinical trial to assess the effect of MR antagonism on atherosclerosis in type II diabetes (DM). In Aim 1, we will test the effect of the MR antagonist Eplerenone (Epl) or placebo on progression of atherosclerosis using high resolution MRI. Key secondary outcomes will include central aortic blood pressure, pulse wave velocity, and measures of insulin resistance while tertiary measures include novel makers of heart failure predisposition. In Aim 2, we hypothesize that expression of monocyte miRNAs and macrophage phenotype may serve as markers of risk, disease progression, and response to MR antagonist. We propose investigating this in three, linked sub-aims. In Aim 2a, we will investigate the functional significance of single or multiple miRNAs involved in the regulation of MR expression using a promoter- reporter-3'UTR construct of the NR3C2 gene in cultured human macrophages. In Aim 2b, monocyte polarization and inflammatory genes will be compared at 6-weeks in Epl/placebo patients. In Aim 2c, at baseline we will measure the expression of miRNAs in monocytes predicted to regulate NR3C2. In addition we will measure NR3C2 transcript and/or protein expression in the same cells. Differential regulation of miRNAs after 6 weeks of treatment will be measured and used to understand disease progression and therapeutic effects of MR blockade. Using state of the art methods to quantify atherosclerosis with the latest advances in vascular biology, this proposal will offer an unprecedented opportunity to elucidate whether MR blockade is effective in atherosclerosis and further provide much needed insights on pathophysiologically relevant mechanisms and predictors of response. The insights from this study may lead to appropriately designed outcome trials.