VASCULAR SMOOTH MUSCLE PLASTICITY IN NITRIC OXIDE

一氧化氮中血管平滑肌的可塑性

• 批准号: 7382071
• 负责人: GREGORY M DICK
• 金额: $ 15.29万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382071
• 关键词: VASCULAR; SMOOTH; MUSCLE; PLASTICITY; NITRIC

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Effects of hypertension and impaired vascular endothelial function on smooth muscle contraction are not completely understood; particularly what molecular changes may take place. We are investigating the effects of nitric oxide deficiency and hypertension on the expression profile of ion channels in smooth muscle. Rats drink water containing Nw-nitro-L-arginine for 14 days to inhibit nitric oxide production and cause hypertension. Hypertension impairs endothelium-dependent relaxation and augments smooth muscle contraction. Smooth muscle membrane potential is depolarized by hypertension and may be the basis for increased contraction; however, mechanisms responsible are not known. We are testing the hypothesis that hypertension decreases the molecular and functional expression of ion channels in vascular smooth muscle that normally regulate membrane potential. RT-PCR, Western blot, and patch clamp electrophysiology techniques are used to assess ion channel expression at the gene, protein, and functional level. Our data indicate that hypertension decreases molecular and functional expression at least two major types of potassium channels: Ca2+-activated and voltage-dependent K+ channels. Expression of the BK alpha subunit protein, a Ca2+-activated K+ channel, is reduced. Further, this correlates with reduced Ca2+-activated K+ current. Expression of Kv1.5 protein, a voltage-dependent K+ channel, is reduced. This is also supported by reduced voltage-dependent K+ current. These findings suggest that reduced molecular and functional expression of smooth muscle K+ channels may lead to depolarization, augmented contraction, and contribute to the pathogenesis of hypertension. We are currently directing our efforts at determining molecular mechanisms governing these changes in K+ channel expression. This laboratory is uniquely positioned to address the hypothesis and the COBRE grant allows opportunities, resources, and infrastructure to ensure the development of the project and personnel.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。高血压和血管内皮功能受损对平滑肌收缩的影响尚不完全清楚，特别是可能发生的分子变化。我们正在研究一氧化氮缺乏和高血压对平滑肌离子通道表达谱的影响。大鼠饮用含有N-硝基-L-精氨酸的水14天，抑制一氧化氮的产生，引起高血压。高血压损害内皮依赖性舒张并增强平滑肌收缩。平滑肌膜电位因高血压而去极化，可能是收缩增加的基础;然而，负责的机制尚不清楚。我们正在验证这样一个假设，即高血压降低了血管平滑肌中正常调节膜电位的离子通道的分子和功能表达。RT-PCR、蛋白质印迹和膜片钳电生理学技术用于在基因、蛋白质和功能水平上评估离子通道表达。我们的数据表明，高血压降低了至少两种主要类型的钾通道的分子和功能表达：Ca 2+激活的和电压依赖性K+通道。BK α亚基蛋白（一种Ca 2+激活的K+通道）的表达减少。此外，这与降低的Ca 2+激活的K+电流相关。Kv1.5蛋白（一种电压依赖性K+通道）的表达减少。这也得到了电压依赖性K+电流降低的支持。这些结果表明，平滑肌K+通道的分子和功能表达减少可能导致去极化，增强收缩，并有助于高血压的发病机制。我们目前正在努力确定K+通道表达变化的分子机制。该实验室具有独特的定位，以解决假设和COBRE赠款允许的机会，资源和基础设施，以确保项目和人员的发展。