Mineralocorticoid Receptor-Mediated Vascular Insulin Resistance

盐皮质激素受体介导的血管胰岛素抵抗

• 批准号: 8670554
• 负责人: Shawn Brady Bender
• 金额: --
• 依托单位: HARRY S. TRUMAN MEMORIAL VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8670554
• 关键词: Address; Adverse effects; Agonist; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Blood Vessels; Blood flow; Calcium; Cardiac Myocytes; Cardiovascular Abnormalities; Cardiovascular system; Cell Culture Techniques; Clinical; Clinical Trials; Coronary; Coronary heart disease; Coupled; Data; Defect; Development; Diabetes Mellitus; Diet; Employee Strikes; Endothelin-1; Event; Fatty acid glycerol esters; Fibrosis; Functional Imaging; Functional disorder; Future; General Population; Glucose tolerance test; Healthcare Systems; High Prevalence; Homeostasis; Hypertension; Impairment; In Vitro; Incidence; Infarction; Insulin Resistance; Knock-out; Knockout Mice; Knowledge; L-Type Calcium Channels; Laboratories; Ligands; Measures; Mediating; Mediator of activation protein; Microcirculation; Microvascular Dysfunction; Mineralocorticoid Receptor; Molecular; Mus; Myocardial Ischemia; Myocardial perfusion; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; Patients; Play; Population; Prevention; Protein-Serine-Threonine Kinases; Receptor Activation; Receptor Signaling; Renin-Angiotensin-Aldosterone System; Reporting; Rho-associated kinase; Role; Signal Transduction; Site; Smooth Muscle Myocytes; Spironolactone; Sucrose; Sudden Death; Techniques; Testing; Therapeutic; Vascular Diseases; Vasoconstrictor Agents; Veterans; Work; arteriole; diabetic patient; endothelial dysfunction; eplerenone; feeding; improved; in vivo; innovation; man; mortality; mouse model; novel; patient population; public health relevance; response; therapeutic target; translational study; vasoconstriction; voltage

DESCRIPTION (provided by applicant): Coronary microvascular dysfunction is an early and persistent defect in states of insulin resistance (IR) that are closely associated with inappropriate activation of the renin-angiotensin-aldosterone system (RAAS). Thus, RAAS activation is a major factor in IR-associated vascular dysfunction, acting via several mechanisms including oxidative stress, fibrosis, endothelial dysfunction and activation of serine kinases such as Rho kinase (ROK). Much existing evidence implicates angiotensin II involvement in these adverse effects; however, accumulating evidence demonstrates pronounced effects of aldosterone acting through vascular mineralocorticoid receptors (MR) as a putative mediator of vascular dysfunction in states of IR. In clinical trials, MR antagonism reduced cardiovascular mortality via unknown mechanisms. Furthermore, recent evidence demonstrates a pronounced effect of MR antagonism to improve coronary flow reserve (CFR) in diabetic patients. The exact mechanism(s) underlying MR-mediated coronary vascular dysfunction; however, remain unclear. Mounting evidence suggests that MR signaling is a primary regulator of cellular calcium homeostasis and contractility. Specifically, MR signaling appears to be a tonic regulator of L-type calcium channel (CaV1.2) function/expression in cardiomyocytes. Our recent work demonstrates that increased activation of coronary vascular MR by aldosterone leads to increased agonist- and CaV1.2-mediated coronary vasoconstrictor responsiveness, similar to that noted in states of IR. Furthermore, our data demonstrate direct activation of ROK, a primary modulator of calcium sensitivity, by MR signaling in vascular smooth muscle cells (VSMC). Therefore, this proposal seeks to investigate novel molecular mechanisms by which VSMC MR signaling promotes VSMC hypercontractility, increased coronary vasoconstriction and reductions in CFR associated with IR. We hypothesize that inappropriate activation of vascular, specifically VSMC, MRs plays a central role in the development of VSMC hypercontractility via the modulation of calcium influx and sensitivity in IR. A corollary to this hypothesis is that MR-dependent signaling in VSMC directly mediates coronary dysfunction and the impairment of coronary blood flow control in states of IR. In our proposal, we will utilize a novel, innovative VSMC-specific MR knockout (VSMC MR KO) mouse model coupled with state-of-the-art microvascular imaging and functional techniques, to evaluate the effect of MR signaling (activated by exogenous aldosterone or diet-induced IR) to modulate VSMC calcium handling, coronary arteriolar function ex vivo and CFR in vivo. To address Specific Aim 1, we will examine the relationship between MR activation and CaV1.2 channel function/expression and ROK activation in primary cultured VSMC, freshly dispersed murine coronary VSMC and intact coronary arterioles. These parameters will be correlated to functional measures including arteriolar vasoconstriction, blood pressure and CFR. Specific Aim 2 will extend these findings and address the role of MR activation in VSMC in IR as a primary mediator of IR-associated coronary hypercontractility/dysfunction and its relationship to arteriolar function and CFR. IR will be induced in wild-type and VSMC MR KO mice with a high-fat, high-sucrose diet and will be assessed by glucose tolerance testing.

描述（由申请人提供）：