REGULATION OF CORONARY ARTERY MYOGENIC TONE BY PKG

PKG 对冠状动脉肌原张力的调节

• 批准号: 6298954
• 负责人: MARK STEPHEN TAYLOR
• 金额: $ 3.48万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6298954
• 关键词: cGMP dependent protein kinase; coronary artery; enzyme activity; enzyme inhibitors; enzyme mechanism; heart circulation; muscle tone; postdoctoral investigator; potassium channel; tissue /cell culture; vascular smooth muscle; vasomotion

Maintenance of adequate coronary artery blood flow is essential for life. Nitric oxide (NO) may play a critical role in the regulation of flow by opposing vascular smooth muscle (VSM) contraction and restricting the development of coronary artery tone. In fact, enhanced tonic release of NO from coronary endothelium is believed to account, at least in part, for the cardioprotective effect of circulating estrogen in premenopausal women. It is widely believed that the vasodillatory influence of NO is mediated predominantly through the action of cGMP dependent protein kinase (PKG) in smooth muscle cells. However, due primarily to the lack of adequately selective inhibitors, the contribution of PKG to the regulation of vascular tone remains unclear.. New peptide inhibitors of PKG, recently developed in the laboratory of Dr. Wolgang Dostmann at the University of Vermont, may provide the selective tools needed to discern PKG dependence. These peptides are composed of potent, substrate-competitive PKG inhibitor sequences linked to carrier sequences (often referred to as "Trojan horse" peptides) that facilitate cellular uptake. Recent preliminary studies have revealed that the novel PKG inhibitor peptide, DT-3, effectively permeates cultured vascular smooth muscle cells and selectively inhibits PKG activity. In this project, specific PKG inhibitors including DT-3 will be employed to assess the role of PKG action will subsequently be addressed, primarily focusing on PKG dependent activation of Ca2+ sensitive potassium channels (K/Ca). The findings of this study will provide valuable insights into the fundamental mechanisms that determine cardiac blood flow.

维持足够的冠状动脉血流对生命至关重要。一氧化氮（NO）可能通过相反的血管平滑肌（VSM）收缩并限制冠状动脉张力的发展在流动中起关键作用。实际上，据信至少部分地说，从冠状动脉内皮中释放了NO的补品释放增强，因为循环雌激素在绝经前妇女中的心脏保护作用。人们普遍认为，NO的血管舒张作用主要是通过平滑肌细胞中CGMP依赖性蛋白激酶（PKG）的作用来介导的。但是，主要是由于缺乏足够的选择性抑制剂，PKG对血管张力调节的贡献尚不清楚。。。PKG的新肽抑制剂最近在佛蒙特大学的Wolgang Dostmann博士实验室开发的新肽抑制剂，可能会为识别PKG依赖提供所需的精选工具。这些肽由与载体序列相关的有效的底物竞争性PKG抑制剂序列（通常称为“特洛伊木马”肽），可促进细胞摄取。最近的初步研究表明，新型的PKG抑制剂肽DT-3有效地渗透到培养的血管平滑肌细胞并选择性地抑制PKG活性。在该项目中，将采用包括DT-3在内的特定PKG抑制剂评估PKG作用的作用，后来将解决CA2+敏感钾通道（K/CA）的依赖性依赖PKG的激活。这项研究的发现将为决定心脏血流的基本机制提供宝贵的见解。