REGULATION OF CORONARY ARTERY MYOGENIC TONE BY PKG

PKG 对冠状动脉肌原张力的调节

• 批准号: 6530609
• 负责人: MARK STEPHEN TAYLOR
• 金额: $ 4.42万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6530609
• 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量对于生命至关重要。一氧化氮 (NO) 可能通过对抗血管平滑肌 (VSM) 收缩和限制冠状动脉张力的发展，在血流调节中发挥关键作用。事实上，冠状动脉内皮的一氧化氮的强直性释放被认为至少部分地解释了绝经前女性循环雌激素的心脏保护作用。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) 的作用介导的。然而，主要由于缺乏足够选择性的抑制剂，PKG 对血管张力调节的贡献仍不清楚。佛蒙特大学 Wolgang Dostmann 博士实验室最近开发的新型 PKG 肽抑制剂可能会提供以下作用：辨别 PKG 依赖性所需的选择性工具。这些肽由有效的底物竞争性 PKG 抑制剂序列组成，这些序列与促进细胞摄取的载体序列（通常称为“特洛伊木马”肽）相连。最近的初步研究表明，新型PKG抑制肽DT-3可有效渗透培养的血管平滑肌细胞并选择性抑制PKG活性。在该项目中，将采用包括 DT-3 在内的特定 PKG 抑制剂来评估 PKG 作用的作用，随后将解决该问题，主要关注 Ca2+ 敏感钾通道 (K/Ca) 的 PKG 依赖性激活。这项研究的结果将为决定心脏血流量的基本机制提供有价值的见解。