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

基本信息

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
项目类别：
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

项目摘要

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）：高血压的发生率（HTN）随着年龄的增长而急剧增加，在老年人中受到了很大的治疗，并且对发病率产生了重大贡献和我们老化社会的死亡率。血管衰老的特征是血管紧张素II（血管静脉）信号增强，血管氧化应激增加以及血管张力增加和收缩。驱动这种老化的血管表型的刺激尚不清楚，也没有策略可以阻止人类的动脉衰老。矿物皮质激素受体（MR）通过结合肾脏中的激素醛固酮（ALDO）来调节血压（BP）以促进钠保留率。我们先前在人血管平滑肌细胞（SMC）中鉴定出功能性MR，发现SMC-MR可以通过ANGII直接激活，并开发了一种具有诱导性，SMC特异性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BP衰老诱导的上升。初步数据表明，AngII以PKC依赖性方式激活MR，这表明了SMC-MR激活的新型配体独立的机制。新的数据显示，L型钙通道（LTCC）表达降低和电流密度，随着衰老的衰老，CA激活的Cl通道TMEM16A表达的损失，以及对肠系膜细胞中LTCC激活的钙和收缩反应降低，而老年SMC-MR-KO小鼠的钙和收缩反应。此外，来自老化的SMC-MR-KO小鼠的血管降低了NADPH-氧化酶亚基NOX2的表达以及基底和ANGII诱导的氧化应激。基于这些数据，我们建议测试新的假设，即在老化的脉管系统中，SMC-MR通过PKC直接通过PKC介导的磷酸化直接激活，并调节LTCC，TMEM16A和NOX2表达和活动，从而促进血管氧化应激压力和相关的增长，从而促进了血管氧化压力和相关的增加。我们建议通过调查三个特定目标来检验这一假设：SA1）。 SMC-MR的ANGII激活机制； SA2）SMC-MR血管离子通道的调节以及对血管张力和衰老收缩的影响； SA3）SMC-MR对血管氧化应激的贡献以及衰老的作用在调节血管张力和BP中的作用。我们建议在新鲜分离的细胞和整个血管中使用分子方法在每个目标中以及在SA3中的体内遥测研究来探索对血压的影响。由于SMC-MR缺失比药理MR拮抗剂更有效地阻止ANGII诱导的HTN，并且广泛使用MR拮抗剂受到肾脏MR Blockade的高钾血性的限制，因此了解SMC-MR被激活并直接对全身HTN疗法识别出比现在更有效的药物，尤其是在当前的药物中，该机制可以直接识别出更高的HTN治疗。