Mineralocorticoid receptor-dependent coronary vascular dysfunction in obesity

冠状动脉血流控制受损是肥胖/代谢综合征患者心脏死亡率的独立预测因素。最新研究 来自我们的实验室和其他人证明了盐皮质激素受体(MR)信号在 肥胖和代谢综合征(METS)的冠状动脉血管功能障碍。具体地说，对抗先生 改善冠脉血管扩张剂反应性的机制尚不清楚。最近的证据表明，血管 细胞，特别是平滑肌细胞(SMC)，MR信号在血管离子通道表达和 功能。冠脉整体血流控制依赖于微血管K+通道的功能表达， 尤其是电压门控K+(Kv)通道，它是SMC机电耦合和 微血管张力。我们的初步数据提供了冠状动脉Kv依赖MR损害的第一个证据 通道，特别是KV1，与甲硫氨酸相关的功能表达受损的这些通道一致。 基于这些初步发现，我们建议检验SMC MR依赖于 信号转导在蛋氨酸冠脉微血管功能障碍中起重要作用。为了实现我们的目标，我们 将研究以下一组特定目标：目标1将确定SMC MR依赖的细胞和分子 利用处理过的雄性和雌性小鼠的组织在蛋氨酸代谢综合征中引起冠状动脉功能障碍的机制 用MR激动剂醛固酮或西式饮食(WD)喂养诱发MET。SMC MR的参与 信号将在SMC特异性MR缺失的小鼠中进行评估。具体地说，这些研究将评估SMC MR对培养的新生微血管SMC中Kv/KV1通道功能表达的调节 研究、膜片钳电生理学、分子/细胞/基因组技术以及冠脉血流 活体成像/超声心动图。AIM 2的研究将利用瘦肉型和蛋氨酸型Ossabaw猪 MR拮抗法阐明MR依赖信号在冠状动脉血管扩张中的作用 蛋氨酸对体内心肌血流量和氧平衡的阻力和控制受损。这些研究将 参与清醒、慢性器械和开胸猪的活体研究以评估冠状动脉 对(病理性)生理刺激的血管运动反应，包括心脏代谢增加(即运动)， 冠脉灌流压升高(即自动调节)和心肌缺血。更多的研究将 评估血流控制的变化是否与心功能的变化相对应。这些在概念上的创新 研究将结合机械性细胞型特异性基因敲除小鼠的研究和临床相关的体内研究 因此提供了综合和补充措施，以解决中央 假设和目标。总之，拟议的目标将提供对 (病理)生理性机电耦合与冠脉血流调节。此外，结果表明， 为创新治疗干预措施减少冠状动脉病变的发生率和影响提供直接依据 以及不断增加的肥胖/甲型肝炎患者的心脏并发症。

Impaired coronary flow control is an independent predictor of cardiac mortality in obesity/MetS. Recent studies from our laboratory and others demonstrate a deleterious role for mineralocorticoid receptor (MR) signaling in coronary vascular dysfunction in obesity and the metabolic syndrome (MetS). Specifically, MR antagonism improves coronary vasodilator responsiveness by unclear mechanisms. Recent evidence suggests that vascular cell, specifically smooth muscle cell (SMC), MR signaling plays a role in vascular ion channel expression and function. Overall coronary flow control is dependent on the functional expression of microvascular K+ channels, in particular voltage-gated K+ (Kv) channels, which are critical mediators of SMC electromechanical coupling and microvascular tone. Our preliminary data provide the first evidence of MR-dependent impairment of coronary Kv channels, specifically Kv1, consistent with MetS-associated impaired functional expression of these channels. Based on these preliminary findings we propose to examine the central hypothesis that SMC MR-dependent signaling significantly contributes to coronary microvascular dysfunction in MetS. To accomplish our goal, we will examine the following set of Specific Aims: Aim 1 will determine SMC MR-dependent cellular and molecular mechanisms responsible for coronary dysfunction in MetS utilizing tissues from male and female mice treated with the MR agonist aldosterone or after western diet (WD) feeding to induce MetS. Involvement of SMC MR signaling will be evaluated in mice with SMC-specific MR deletion. Specifically, these studies will evaluate SMC MR-dependent modulation of Kv/Kv1 channel functional expression in cultured SMC, freshly isolated microvessel studies, patch clamp electrophysiology, and molecular/cellular/genomic techniques as well as coronary flow imaging/echocardiography in vivo. Studies in Aim 2 will utilize lean and MetS Ossabaw swine with and without MR antagonism to elucidate the contribution of MR-dependent signaling to augmented coronary vascular resistance and impaired control of myocardial blood flow and oxygen balance in vivo in MetS. These studies will involve in vivo studies in conscious, chronically instrumented and open-chest swine to evaluate coronary vasomotor responses to (patho)physiologic stimuli including increased cardiac metabolism (i.e., exercise), increased coronary perfusion pressure (i.e., autoregulation), and myocardial ischemia. Additional studies will evaluate if changes in flow control correspond to changes in cardiac function. These conceptually innovative studies will combine mechanistic cell-type specific knockout mouse studies with clinically relevant in vivo studies of myocardial oxygen balance thereby providing integrative and complementary measures to address the central hypothesis and Aims. Together, the proposed Aims will provide novel insight into mechanisms of (patho)physiologic electromechanical coupling and coronary flow regulation in MetS. Further, results stand to provide direct rationale for innovative therapeutic interventions to reduce the incidence and impact of coronary and cardiac complications in the ever increasing population of obese/MetS patients.