Smooth Muscle Mineralocorticoid Receptors in Vascular Aging and Hypertension

血管老化和高血压中的平滑肌盐皮质激素受体

• 批准号: 8904701
• 负责人: Iris Z Jaffe
• 金额: $ 56.02万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8904701
• 关键词: Adverse effects; Age; Aging; Agonist; Aldosterone; Angiotensin II; Antioxidants; Automobile Driving; Binding; Biological Assay; Blood Pressure; Blood Vessels; Calcium; Cardiovascular Diseases; Cell Fraction; Cell Line; Cells; Chromatin; Data; Dominant-Negative Mutation; Elderly; Genetically Engineered Mouse; Goals; Health; Hormones; Human; Hypertension; Image; Imaging Techniques; Immunoblotting; In Vitro; Incidence; Ion Channel; Kidney; L-Type Calcium Channels; Ligands; Measures; Mediating; Medicine; Membrane; Membrane Proteins; Mesentery; Mineralocorticoid Receptor; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Muscle Cells; Mutation; Myocardial Infarction; Myography; NADPH Oxidase; Oxidative Stress; PKC Phosphorylation Site; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphorylation; Population; Publishing; Receptor Activation; Regulation; Reporter; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Role; Signal Transduction; Small Interfering RNA; Smooth Muscle; Smooth Muscle Myocytes; Societies; Sodium; Stimulus; Stroke; Telemetry; Testing; aged; base; blood pressure regulation; density; high risk; hyperkalemia; hypertension treatment; in vivo; innovation; ion channel blocker; knock-down; mRNA Expression; mortality; mouse model; mutant; novel; older patient; patch clamp; pressure; prevent; promoter; protective effect; response; vasoconstriction

DESCRIPTION (provided by applicant): The incidence of hypertension (HTN) increases dramatically with age, is poorly treated in the elderly, and contributes significantly to morbidity and mortality in our aging society. Vascular aging is characterized by enhanced angiotensin II (AngII) signaling, increased vascular oxidative stress, and increased vascular tone and contraction. The stimuli driving this aging vascular phenotype are not well understood and no strategy is known to retard arterial aging in humans. Mineralocorticoid receptors (MR) regulate blood pressure (BP) by binding the hormone aldosterone (Aldo) in the kidney to promote sodium retention. We previously identified functional MR in human vascular smooth muscle cells (SMC), discovered that SMC-MR can be directly activated by AngII, and developed a novel mouse model with inducible, SMC-specific deletion of MR (SMC- MR-KO). SMC-MR deletion prevented AngII-induced HTN, vascular oxidative stress and mesenteric vessel contraction and the aging-induced rise in BP. Preliminary data show that AngII activates MR in human SMC in a PKC -dependent manner suggesting a novel ligand-independent mechanism of SMC-MR activation. New data reveals decreased L-type calcium channel (LTCC) expression and current density, a loss of the rise in expression of the Ca-activated Cl channel TMEM16A with aging, and decreased calcium and contractile responses to LTCC activation in mesenteric cells and vessels from aged SMC-MR-KO mice. Furthermore vessels from aged SMC-MR-KO mice have decreased expression of the NADPH-oxidase subunit Nox2 and lower basal and AngII-induced oxidative stress. Based on these data, we propose to test the novel hypothesis that in the aging vasculature, SMC-MR is directly activated by AngII via PKC -mediated phosphorylation and regulates LTCC, TMEM16A and Nox2 expression and activity, promoting the age-associated increase in vascular oxidative stress and contraction, thereby contributing to hypertension. We propose to test this hypothesis with three specific aims investigating: SA1). The mechanism of AngII activation of SMC-MR; SA2) SMC-MR regulation of vascular ion channels and the impact on vascular tone and contraction with aging; and SA3) SMC-MR contribution to vascular oxidative stress with aging and the role in modulating vascular tone and BP. We propose to use molecular approaches in freshly isolated cells and whole vessels in each aim and in vivo telemetry studies in SA3 to explore the impact on blood pressure. Since SMC-MR deletion was more effective in blocking AngII-induced HTN than pharmacologic MR antagonist and widespread use of MR antagonists is limited by hyperkalemia from renal MR blockade, understanding the mechanisms by which SMC-MR is activated and directly contributes to systemic BP could identify novel HTN therapies that are more effective and safer than current drugs, particularly in the elderly.

描述（由申请人提供）：高血压（HTN）的发病率随着年龄的增长而急剧增加，老年人的治疗效果不佳，并且显着增加发病率 和老龄化社会的死亡率。血管老化的特点是血管紧张素 II (AngII) 信号传导增强、血管氧化应激增加以及血管张力和收缩增加。驱动这种老化血管表型的刺激因素尚不清楚，也没有已知的策略可以延缓人类动脉老化。盐皮质激素受体 (MR) 通过与肾脏中的醛固酮 (Aldo) 激素结合来促进钠潴留来调节血压 (BP)。我们之前在人血管平滑肌细胞（SMC）中鉴定了功能性MR，发现SMC-MR可以被AngII直接激活，并开发了一种具有可诱导的、SMC特异性MR缺失的新型小鼠模型（SMC-MR-KO）。 SMC-MR 缺失可防止 AngII 诱导的 HTN、血管氧化应激和肠系膜血管收缩以及衰老引起的血压升高。初步数据显示，AngII 以 PKC 依赖性方式激活人 SMC 中的 MR，这表明 SMC-MR 激活存在一种新的配体独立机制。新数据揭示了 L 型钙通道 (LTCC) 表达和电流密度下降，Ca 激活 Cl 通道 TMEM16A 的表达随着年龄的增长而增加，并且肠系膜细胞和血管中对 LTCC 激活的钙和收缩反应降低。老年 SMC-MR-KO 小鼠。此外，老年 SMC-MR-KO 小鼠的血管中 NADPH 氧化酶亚基 Nox2 的表达降低，基础氧化应激和 AngII 诱导的氧化应激也降低。基于这些数据，我们建议测试一个新的假设，即在衰老的血管系统中，SMC-MR通过PKC介导的磷酸化直接被AngII激活，并调节LTCC、TMEM16A和Nox2的表达和活性，促进与年龄相关的血管的增加。氧化应激和收缩，从而导致高血压。我们建议通过三个具体的研究目标来检验这一假设：SA1)。 SMC-MR的AngII激活机制； SA2) SMC-MR对血管离子通道的调节以及随衰老对血管张力和收缩的影响； SA3) SMC-MR 对衰老过程中血管氧化应激的贡献以及调节血管张力和血压的作用。我们建议在每个目标中使用新鲜分离的细胞和整个血管的分子方法以及 SA3 中的体内遥测研究来探索对血压的影响。由于 SMC-MR 缺失在阻断 AngII 诱导的 HTN 方面比药物 MR 拮抗剂更有效，并且 MR 拮抗剂的广泛使用受到肾脏 MR 阻断引起的高钾血症的限制，因此了解 SMC-MR 被激活并直接影响全身血压的机制可以确定比现有药物更有效、更安全的新型 HTN 疗法，特别是对于老年人。