Vascular Calcium Channel Expression in Hypertension

高血压中血管钙通道的表达

• 批准号: 7822226
• 负责人: Nancy J Rusch
• 金额: $ 0.65万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7822226
• 关键词: Affect; American; Angiotensins; Animals; Antihypertensive Agents; Appearance; Arteries; Biological Assay; Blood Pressure; Blood Vessels; Calcium; Calcium Channel; Caliber; Cell surface; Chronic; Complex; Contracts; Development; Dihydropyridines; Disease; Electrophysiology (science); Environmental Risk Factor; Etiology; Faculty; Gene Deletion; Genes; Goals; Grant; Heart failure; Homeostasis; Hour; Hypertension; Image; In Vitro; Inbred SHR Rats; Infusion procedures; Kidney; Kidney Diseases; Knockout Mice; Knowledge; Label; Laboratories; Left Ventricular Hypertrophy; Membrane; Membrane Proteins; Mesenteric Arteries; Mesentery; Methods; Modeling; Molecular; Monitor; Mus; Muscle Cells; Myocardial Infarction; Norepinephrine; Pathogenesis; Proteins; Rattus; Recording of previous events; Recruitment Activity; Renal Circulation; Research Project Grants; Role; Smooth Muscle Myocytes; Splanchnic Circulation; Stroke; Study Section; Surface; Talents; Techniques; Testing; Time; United States; Up-Regulation; Vascular resistance; base; density; design; dihydropyridine; experience; in vivo; insight; intravital video microscopy; member; mouse development; mouse model; novel; overexpression; patch clamp; pressure; protein complex; public health relevance; renal artery; response; vascular bed; vasoconstriction; voltage

DESCRIPTION (provided by applicant): The L-type Ca2+ (CaL) channels are multi-protein complexes that include a pore- forming 11C subunit and smaller ancillary subunits. The ancillary 2 subunits promote the expression of 11C subunits at the surface membrane to increase the number of functional CaL channels. In vascular smooth muscle cells (VSMCs), CaL channels are only sparsely expressed in order to tightly regulate voltage-gated Ca2+ influx and vascular contraction. However, during the development of hypertension, we have shown that CaL channels profoundly upregulate in the VSMCs to fuel abnormal vasoconstriction. The goal of this revised project is to determine the mechanism of CaL channel upregulation in response to rises in blood pressure. We have noted that a specific 2 subunit, 23, selectively and profoundly increases in the mesenteric circulation of angiotensin (Ang II) hypertensive mice. The resulting overabundance of CaL channel 11C23 complexes results in elevated Ca2+ influx and abnormal Ca2+-dependent tone in the small arteries of the affected animals. In fact, pharmacological block of CaL channels sharply reduces blood pressure in Ang II hypertensive mice in vivo, but has little antihypertensive effect in control mice, suggesting a central contribution of CaL channels to the pathogenesis of hypertension. At the reviewers' behest, this revised application is tightly focused on delineated the mechanism of vascular CaL channel abnormalities in hypertensive mice to take advantage of gene deletion models. Aim 1 will determine if an increased number of CaL channel 11C23 complexes is associated with anomalous Ca2+ influx in VSMCs of two mouse models of hypertension. Aim 2 will use 23 knockout mice to determine if the 23 subunit is a requisite contributor to CaL channel upregulation and the development of hypertension. We predict that vascular CaL channel 11C23 complexes will fail to upregulate in response to Ang II or norepinephrine infusion in 23 knockout mice, and that the development of hypertension will be severely blunted. Finally, Aim 3 will utilize a novel microvascular assay that we have developed to monitor CaL channel expression in the VSMCs of single, pressurized mouse mesenteric arteries. Using this unique assay, we will directly test the hypothesis that high intraluminal pressure inhibits the turnover of CaL channels, thereby increasing their expression at the VSMC surface membrane during hypertension. PUBLIC HEALTH RELEVANCE: Sixty million Americans have high blood pressure, which leads to heart attacks, kidney disease and stroke. This research project will determine if a specific molecule in the muscle cells of blood vessels is required for the abnormal appearance of membrane proteins that causes arteries to contract too much, thereby elevating blood pressure to dangerous levels.

描述（由申请人提供）：l型Ca2+ (CaL)通道是多蛋白复合物，包括形成孔隙的11C亚基和更小的辅助亚基。辅助性2亚基促进11C亚基在细胞膜表面的表达，增加功能性CaL通道的数量。在血管平滑肌细胞（VSMCs）中，CaL通道仅稀疏表达，以严格调节电压门控Ca2+内流和血管收缩。然而，在高血压的发展过程中，我们发现VSMCs中的CaL通道深度上调，从而导致血管异常收缩。这个修订项目的目的是确定CaL通道上调的机制，以应对血压升高。我们已经注意到，在血管紧张素（Ang II）高血压小鼠的肠系膜循环中，一个特定的2亚基23选择性地和深刻地增加。由此产生的过多的CaL通道11C23复合物导致Ca2+内流升高和Ca2+依赖性的异常张力在受影响动物的小动脉。事实上，CaL通道的药物阻断在体内可显著降低Ang II型高血压小鼠的血压，但在对照组小鼠中几乎没有降压作用，这表明CaL通道在高血压发病机制中发挥了核心作用。在审稿人的要求下，这一修改后的应用程序主要集中在描述高血压小鼠血管CaL通道异常的机制，以利用基因缺失模型。目的1将确定CaL通道11C23复合物数量的增加是否与两种高血压小鼠模型VSMCs中异常Ca2+内流有关。Aim 2将使用23只基因敲除小鼠来确定23亚基是否是CaL通道上调和高血压发生的必要因素。我们预测，在23基因敲除小鼠中，血管CaL通道11C23复合物在Ang II或去甲肾上腺素输注的反应中将无法上调，并且高血压的发展将严重减弱。最后，Aim 3将利用我们开发的一种新型微血管试验来监测单个加压小鼠肠系膜动脉VSMCs中CaL通道的表达。通过这种独特的实验，我们将直接验证高腔内压抑制CaL通道的周转，从而增加高血压期间VSMC表面膜上CaL通道的表达的假设。公共卫生相关性：6000万美国人患有高血压，高血压会导致心脏病、肾病和中风。该研究项目将确定是否需要血管肌肉细胞中的特定分子来引起膜蛋白的异常外观，从而导致动脉过度收缩，从而将血压升高到危险水平。