MINERALOCORTICOID RECEPTOR ANTAGONISM CLINICAL EVALUATION IN ATHEROSOCLEROSIS (MAGMA)

 描述（由申请人提供）：我们以前已经证明盐皮质激素受体（MR）在动脉粥样硬化的炎症中起重要作用。我们实验室的研究表明单核细胞MR激活在单核细胞/巨噬细胞炎症中的作用。此外，我们已经证明了候选microRNAs（miRNAs）在调节单核细胞中MR（NR 3C 2）基因表达和预测动脉粥样硬化中的关键作用。这些发现表明，miRNA表达预测患者对MR阻断的反应。我们提出了一个随机双盲临床试验，以评估MR拮抗剂对II型糖尿病（DM）动脉粥样硬化的影响。在目标1中，我们将使用高分辨率MRI测试MR拮抗剂依普利酮（Epl）或安慰剂对动脉粥样硬化进展的影响。关键的次要结果包括中心主动脉血压、脉搏波速度和胰岛素抵抗指标，而三级指标包括心力衰竭易感性的新指标。在目标2中，我们假设单核细胞miRNAs的表达和巨噬细胞表型可以作为风险、疾病进展和对MR拮抗剂反应的标志物。我们建议在三个相互关联的次级目标中对此进行调查。在目标2a中，我们将使用NR 3C 2基因的启动子-报告基因-3 'UTR构建体在培养的人巨噬细胞中研究参与MR表达调控的单个或多个miRNA的功能意义。在目标2b中，将在6周时比较Epl/安慰剂患者的单核细胞极化和炎症基因。在目标2c中，在基线时，我们将测量预测调节NR 3C 2的单核细胞中miRNA的表达。此外，我们将测量相同细胞中NR 3C 2转录物和/或蛋白质表达。将测量治疗6周后miRNA的差异调节，并用于了解疾病进展和MR阻断的治疗效果。使用最先进的方法来量化动脉粥样硬化与血管生物学的最新进展，这一建议将提供一个前所未有的机会，以阐明MR阻断是否是有效的动脉粥样硬化，并进一步提供急需的见解病理生理相关的机制和预测反应。本研究的见解可能会导致适当设计的结局试验。

 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.