Mechanisms of Coronary Vasomotor Control

冠状动脉血管舒缩控制机制

• 批准号: 8710335
• 负责人: WILLIAM M CHILIAN
• 金额: $ 35.94万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8710335
• 关键词: 4-Aminopyridine; Address; Adenosine; Aerobic; Apical; Arteries; Automobile Driving; Blood Vessels; Blood flow; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cell Respiration; Chronic; Clinical Trials; Coronary; Coronary heart disease; Couples; Coupling; Data; Deterioration; Development; Drug usage; Electrocardiogram; Electrophysiology (science); Family; Functional disorder; Goals; Heart; Hydrogen Peroxide; Hypoxia; Impairment; In Vitro; Ion Channel; Knockout Mice; Kv1.2' channel; Link; Measures; Mediating; Metabolic; Metabolism; Microvascular Dysfunction; Mitochondria; Mus; Myocardial; Myocardial Ischemia; Myocardial perfusion; Myocardial tissue; Myocardium; Oxidation-Reduction; Patients; Phenotype; Physiology; Play; Process; Production; Regulation; Reporting; Role; Signal Transduction; Smooth Muscle; Syndrome; System; Testing; Tetanus Helper Peptide; Thinking; Transgenic Organisms; Vascular Smooth Muscle; Vasodilation; Vasomotor; Work; arteriole; db/db mouse; diabetic; diabetic cardiomyopathy; feeding; functional disability; gain of function; heart metabolism; in vivo; indexing; loss of function; member; prevent; public health relevance; research study; sensor; tissue oxygenation

DESCRIPTION (provided by applicant): The overarching aim of this proposal is to elucidate vascular effectors that transduce metabolic signals that enable the connection of flow to cardiac metabolism-metabolic dilation. The heart is dependent on metabolic dilation for aerobic energy production because anaerobic reserve is virtually non-existent; however, the effectors responsible for coupling flow to metabolism in the heart remain unidentified. The matching of flow to metabolism is important and may play a role in microvascular diseases in the heart. We have suggested that Kv channels transduce the H2O2 metabolic signal into redox- mediated coronary metabolic vasodilation. Because certain members of the Kv1 family of channels are redox sensitive (e.g., Kv1.2, 1.3 and 1.5), our first goal will determine, which redox sensing Kv channels transduce metabolic signals to flow in the heart. This aim will be tested using loss and gain of function approaches. Loss of function will use mice null for Kv1.5 and 1.3 channels, and heterozygous null for Kv1.2 channels (Kv1.2-/- is lethal), and gain of function will study of expression of the specific ion channel using a smooth muscle specific Tet On system driving expression of the Kv channel. We have found that metabolic dilation in the diabetic db/db mouse is impaired and that expression of Kv1.2, 1.3, and 1.5 channels is substantially decreased in arteries of these mice. Our goal in the second aim is to perform gain of function studies in db/db mice by expressing Kv1.5, 1.2 and/or Kv1.3 channels using the Tet inducible system in smooth muscle. Our overall strategy is to measure the relationship between cardiac work, and myocardial blood flow and tissue oxygenation along with evaluating measures of cardiac function and myocardial ischemia. We also will perform in vitro studies to determine the production of vasoactive metabolites from cardiac myocytes, vascular reactivity of isolated arterioles and electrophysiological parameters in smooth muscle. This integrated approach-from electrophysiology to in vivo flow regulation should enable answers regarding basic coronary physiology and flow regulation, as well as potential therapies for diabetic cardiomyopathy.

描述（由申请人提供）：本提案的总体目标是阐明抑制代谢信号的血管效应物，这些代谢信号使血流与心脏代谢-代谢扩张联系起来。心脏依赖于代谢扩张来产生有氧能量，因为无氧储备几乎不存在;然而，负责将心脏中的流动耦合到代谢的效应器仍然未被识别。血流与代谢的匹配很重要，可能在心脏微血管疾病中发挥作用。我们认为Kv通道将H2 O2代谢信号转化为氧化还原介导的冠状动脉代谢性血管舒张。因为Kv 1通道家族的某些成员是氧化还原敏感的（例如，Kv 1.2、1.3和1.5），我们的第一个目标将确定哪些氧化还原传感Kv通道使代谢信号在心脏中流动。这一目标将使用功能的丧失和获得方法进行测试。功能丧失将使用Kv1.5和1.3通道无效的小鼠，以及Kv1.2通道无效的杂合小鼠（Kv1.2-/-是致死的），而功能获得将使用平滑肌特异性泰特On系统研究特定离子通道的表达，该系统驱动Kv通道的表达。我们发现糖尿病db/db小鼠的代谢扩张受损，并且这些小鼠的动脉中Kv1.2、1.3和1.5通道的表达显著降低。我们的第二个目标是通过在平滑肌中使用泰特诱导系统表达Kv1.5、1.2和/或Kv1.3通道来在db/db小鼠中进行功能获得研究。我们的总体策略是测量心脏功与心肌血流量和组织氧合之间的关系，同时沿着评估心脏功能和心肌缺血的测量。我们还将进行体外研究，以确定心肌细胞的血管活性代谢产物的产生，离体小动脉的血管反应性和平滑肌的电生理参数。这种从电生理学到体内血流调节的综合方法应该能够回答关于基本冠状动脉生理学和血流调节以及糖尿病心肌病的潜在治疗方法的问题。