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: 8759190
• 负责人: Iris Z Jaffe
• 金额: $ 61.45万
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8759190
• 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; 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; public health relevance; 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）的发病率随年龄增长而显著增加，老年人治疗不良，并显著增加发病率 和死亡率之间的关系。血管老化的特征在于增强的血管紧张素II（AngII）信号传导、增加的血管氧化应激以及增加的血管张力和收缩。驱动这种老化血管表型的刺激还没有很好的理解，也没有已知的策略来延缓人类动脉老化。盐皮质激素受体（MR）通过结合肾脏中的激素醛固酮（Aldo）来调节血压（BP），以促进钠潴留。我们先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，并开发了具有可诱导的SMC特异性MR缺失（SMC-MR-KO）的新型小鼠模型。SMC-MR缺失阻止AngII诱导的HTN、血管氧化应激和肠系膜血管收缩以及衰老诱导的BP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激活的新的配体非依赖性机制。新的数据揭示了降低L型钙通道（LTCC）的表达和电流密度，钙激活的Cl通道TMEM 16 A的表达增加与衰老的损失，并降低钙和收缩反应LTCC激活肠系膜细胞和血管从老年SMC-MR-KO小鼠。此外，来自老年SMC-MR-KO小鼠的血管具有降低的NADPH氧化酶亚基Nox 2表达和较低的基础和AngII诱导的氧化应激。基于这些数据，我们提出了一个新的假设，即在老化的血管系统中，SMC-MR通过PKC介导的磷酸化直接被AngII激活，并调节LTCC、TMEM 16 A和Nox 2的表达和活性，促进血管氧化应激和收缩的年龄相关性增加，从而导致高血压。我们建议用三个具体的研究目标来检验这一假设：SA 1）。血管紧张素II激活SMC-MR的机制; SA 2）SMC-MR对血管离子通道的调节以及对血管张力和收缩的影响;以及SA 3）SMC-MR对血管氧化应激的贡献以及在调节血管张力和BP中的作用。我们建议在每个目标的新鲜分离的细胞和整个血管中使用分子方法，并在SA 3中进行体内遥测研究，以探索对血压的影响。由于SMC-MR缺失在阻断AngII诱导的HTN方面比药理学MR拮抗剂更有效，并且MR拮抗剂的广泛使用受到肾MR阻断引起的高钾血症的限制，因此了解SMC-MR被激活并直接导致全身BP的机制可以确定比当前药物更有效和更安全的新型HTN治疗，特别是在老年人中。