Mineralocorticoid receptor-dependent coronary vascular dysfunction in obesity

肥胖症中盐皮质激素受体依赖性冠状血管功能障碍

• 批准号: 10304863
• 负责人: Shawn Brady Bender
• 金额: $ 54.94万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304863
• 关键词: Address; Adult; Agonist; Aldosterone; Area; Attenuated; Blood Pressure; Blood Vessels; Blood flow; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cell Culture Techniques; Cells; Chest; Chronic; Congestive Heart Failure; Conscious; Coronary; Coronary Arteriosclerosis; Coupling; Data; Defect; Development; Echocardiography; Electrophysiology (science); Epidemic; Equilibrium; Event; Exercise; Exhibits; Family suidae; Female; Functional disorder; Future; Genomics; Goals; Heart failure; Homeostasis; Human; Hypertension; Image; Immunohistochemistry; Impairment; In Vitro; Incidence; Infusion procedures; Ion Channel; Knockout Mice; Laboratories; Left; Measures; Mediator of activation protein; Metabolic syndrome; Metabolism; Microvascular Dysfunction; Mineralocorticoid Receptor; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Obesity; Obesity associated cardiovascular disease; Oxygen; Pathologic; Patients; Perfusion; Physiologic intraventricular pressure; Physiological; Play; Potassium Channel; Preparation; Receptor Activation; Receptor Signaling; Regulation; Renin-Angiotensin-Aldosterone System; Research; Role; Signal Transduction; Smooth Muscle Myocytes; Spironolactone; Stimulus; Stroke; Techniques; Testing; Therapeutic Intervention; Thinness; Tissues; Troponin; United States; Vascular Diseases; Vascular resistance; Vasomotor; antagonist; base; biophysical properties; cell type; clinically relevant; clinically significant; coronary perfusion; coronary vasodilator; diabetic; eplerenone; feeding; functional disability; heart function; heart metabolism; improved; in vivo; innovation; insight; instrument; male; mortality; myocardial injury; new therapeutic target; novel; obese person; pandemic disease; patch clamp; patient population; preservation; pressure; prevent; programs; response; sudden cardiac death; voltage; western diet

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.

冠状动脉血流控制受损是肥胖/代谢综合征患者心源性死亡率的独立预测因子。最近的研究 来自我们实验室和其他实验室的研究表明，盐皮质激素受体（MR）信号在 肥胖和代谢综合征（MetS）中的冠状动脉血管功能障碍。具体而言，MR拮抗作用 通过不清楚的机制改善冠状动脉血管舒张反应性。最近的证据表明， 细胞，特别是平滑肌细胞（SMC），MR信号在血管离子通道表达中起作用， 功能总体冠状动脉流量控制依赖于微血管K+通道的功能表达， 特别是电压门控K+（Kv）通道，其是SMC机电耦合的关键介质， 微血管张力我们的初步数据提供了冠状动脉Kv的MR依赖性损害的第一个证据， 通道，特别是Kv 1，与MetS相关的这些通道的功能表达受损一致。 基于这些初步的发现，我们建议检查中心假设，即SMC MR依赖性 信号传导显著促进MetS中的冠状动脉微血管功能障碍。为了实现我们的目标，我们 将检查以下一组特定目标：目标1将确定SMC MR依赖的细胞和分子 在MetS中使用来自处理的雄性和雌性小鼠的组织负责冠状动脉功能障碍的机制 用MR激动剂醛固酮或在西方饮食（WD）喂养后诱导MetS。SMC MR的参与 将在具有SMC特异性MR缺失的小鼠中评价信号传导。具体而言，这些研究将评估SMC 在培养的SMC、新鲜分离的微血管中MR依赖性调节Kv/Kv 1通道功能表达 研究、膜片钳电生理学和分子/细胞/基因组技术以及冠状动脉血流 在体内成像/超声心动图。目标2中的研究将利用瘦肉型和MetS Ossabaw猪， MR拮抗作用以阐明MR依赖性信号对增强冠状动脉血管的贡献 在MetS中，体内心肌血流和氧平衡的控制受损。这些研究将 涉及在清醒、长期使用器械和开胸猪中进行的体内研究，以评价冠状动脉 对（病理性）生理刺激的血管扩张反应包括增加的心脏代谢（即，锻炼）， 增加的冠状动脉灌注压（即，自动调节）和心肌缺血。其他研究将 评估血流控制的变化是否对应于心脏功能的变化。这些概念上的创新 研究将结合联合收割机机制细胞类型特异性敲除小鼠研究和临床相关的体内研究 心肌氧平衡，从而提供综合和补充措施， 假设和目标。总之，拟议的目标将提供新的见解机制， 代谢综合征中的（病理）生理机电耦合和冠状动脉血流调节。此外，结果表明， 为创新性治疗干预提供直接依据，以减少冠状动脉疾病的发生率和影响 和心脏并发症的风险。

项目成果

Chronic High-Rate Pacing Induces Heart Failure with Preserved Ejection Fraction-Like Phenotype in Obese Ossabaw Swine.

慢性高速率起搏在肥胖奥萨巴猪中诱导心力衰竭并保留射血分数样表型。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Tune,JohnathanD;Goodwill,AdamG;Baker,HanaE;Dick,GregoryM;Warne,CooperM;Bailey,ChastidyA;Klasing,JessicaA;Russell,JacobJ;McCallinhart,PatriciaE;Trask,AaronJ;Bender,ShawnB
• 通讯作者: Bender,ShawnB

Linking Coronary Microvascular and Cardiac Diastolic Dysfunction in Diabetes: Are Women More Vulnerable?

糖尿病中冠状动脉微血管和心脏舒张功能障碍之间的联系：女性是否更容易受到影响？

• DOI: 10.2337/dbi18-0053
• 发表时间: 2019
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Bender,ShawnB

Clinical efficacy of tadalafil compared to sildenafil in treatment of moderate to severe canine pulmonary hypertension: a pilot study.

他达拉非与西地那非治疗中度至重度犬肺动脉高压的临床疗效：一项初步研究。

• DOI: 10.1016/j.jvc.2019.05.001
• 发表时间: 2019
• 期刊: Journal of veterinary cardiology : the official journal of the European Society of Veterinary Cardiology
• 作者: Jaffey,JA;Leach,SB;Kong,LR;Wiggen,KE;Bender,SB;Reinero,CR
• 通讯作者: Reinero,CR

Cardiovascular Disease in Obstructive Sleep Apnea: Putative Contributions of Mineralocorticoid Receptors.

• DOI: 10.3390/ijms24032245
• 发表时间: 2023-01-23
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Badran, Mohammad;Bender, Shawn B.;Gozal, David
• 通讯作者: Gozal, David