Roles of Endothelial and Smooth Muscle KATP Channels in Myocardial Ischemic Injury

内皮和平滑肌 KATP 通道在心肌缺血性损伤中的作用

• 批准号: 10308702
• 负责人: William A Coetzee
• 金额: $ 73.28万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308702
• 关键词: Biochemical; Biochemistry; Biology; Blood Preservation; Blood Vessels; Blood flow; Cardiac; Cell Death; Cellular Assay; Collaborations; Complex; Coronary; Coronary Vessels; Data; Development; Electrophysiology (science); Endothelial Cells; Endothelium; Environment; Event; Functional disorder; Genetic; Goals; Heart; Hypoxia; Infarction; Ion Channel; Ischemia; Ischemic Preconditioning; Joints; Knock-out; Knockout Mice; Mediating; Mitochondria; Modeling; Molecular; Mus; Myocardial; Myocardial Ischemia; Myocardium; Pathway interactions; Pharmacology; Physiological; Play; Positioning Attribute; Proteins; Protocols documentation; Publications; Regulation; Reperfusion Injury; Reperfusion Therapy; Research; Research Personnel; Research Support; Resources; Role; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Stress; Surface; Two-Dimensional Echocardiography; Ventricular; cardioprotection; conditional knockout; coronary vasculature; density; experience; experimental study; heart function; in vivo; insight; interest; ischemic injury; mouse model; novel; preconditioning; pressure; response; tool; trafficking; vascular bed

SUMMARY Sarcolemmal ATP-sensitive K+ (KATP) channels are abundantly expressed in the heart. Several groups have now identified a key role for these channels in mediating cardioprotection against ischemic injury and their participation in the protective mechanism of ischemic preconditioning. In the heart there several different subtypes of KATP channels and little is known about the roles during ischemia and reperfusion. Of particular interest are the KATP channel subtypes present in the coronary smooth muscle (SM) and coronary endothelial cells (EC). There is increasing focus on these coronary channels as a target for blood flow regulation and cardioprotection, yet they are relatively poorly understood. The SM and EC KATP channels are distinct from ventricular KATP channels and they are also distinct from each other. A major barrier to our understanding of their respective roles during a complex event such as myocardial ischemia is the lack of currently available resources specifically to study these two channel subtypes. We have generated novel genetic mouse models that can distinguish these subtypes of KATP channels and show with one of these that EC KATP channels strongly participate in myocardial protection during ischemia/reperfusion. The goal of the proposed studies is systematically to examine the role(s) of the EC and SM KATP channel subtypes in the regulation of coronary blood flow, protection during ischemia and the protective response to ischemic preconditioning. We hypothesize that both EC and SM KATP channel subtypes contribute to the regulation of coronary blood flow and cardioprotection, but through distinctly different mechanisms. Using novel and validated conditional knockout mice, we will specifically target EC or SM KATP channel subtypes. The proposed studies have three Aims. In Aim 1, we will investigate the roles of these two coronary KATP channel subtypes in blood flow during ischemia. We will use isolated, pressurized microvessels and isolated, perfused hearts under normal, hypoxic and ischemic conditions. We will additionally investigate the role of EC and SM KATP channels in the myocardial “no-reflow” phenomenon. Aim 2 will investigate the roles of EC and SM KATP channels in myocardial protection using an in vivo murine I/R model and investigate pathways that regulate infarct development. Aim 3 will investigate the contribution of EC and SM KATP channel subtypes during ischemic preconditioning using an in vivo murine I/R model and cellular assays. We will also examine trafficking of these KATP channel subtypes as a potential protective mechanism and investigate molecular signaling pathways involved. This multi-investigator proposal combines the expertise of three highly established investigators; Dr. Lefer’s extensive expertise with in vivo cardiac ischemia/reperfusion models, and Dr. Coetzee’s track record of studying KATP channels with electrophysiological, biochemical and molecular approaches and Dr. Tinker’s expertise in studying molecular signaling pathways in vascular KATP channels. The proposed studies will provide important molecular insights into the unique functions of coronary KATP channel subtypes under pathophysiological conditions.

总结