Mechanisms of Coronary Vasomotor Control

冠状动脉血管舒缩控制机制

• 批准号: 8578656
• 负责人: WILLIAM M CHILIAN
• 金额: $ 35.81万
• 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/8578656
• 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; Diabetic Angiopathies; 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; 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）：该提案的总体目标是阐明转导代谢信号的血管效应器，这些信号能够将血流与心脏代谢-代谢扩张联系起来。心脏依靠代谢扩张来产生有氧能量，因为无氧储备实际上不存在；然而，负责将血流与心脏代谢耦合的效应器仍不清楚。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 H2O2 代谢信号转导为氧化还原介导的冠状动脉代谢血管舒张。由于 Kv1 通道家族的某些成员对氧化还原敏感（例如 Kv1.2、1.3 和 1.5），因此我们的第一个目标将确定哪些氧化还原感应 Kv 通道将代谢信号转导在心脏中流动。将使用功能损失和增益方法来测试这一目标。功能丧失将使用小鼠 Kv1.5 和 1.3 通道无效，以及 Kv1.2 通道杂合无效（Kv1.2-/- 是致命的），而功能获得将使用平滑模型研究特定离子通道的表达肌肉特异性 Tet On 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 通道的表达显着降低。我们的第二个目标是通过使用平滑肌中的 Tet 诱导系统表达 Kv1.5、1.2 和/或 Kv1.3 通道，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做功、心肌血流量和组织氧合之间的关系，同时评估心脏功能和心肌缺血的指标。我们还将进行体外研究，以确定心肌细胞血管活性代谢物的产生、离体小动脉的血管反应性以及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解答有关基本冠状动脉生理学和血流调节的问题，以及糖尿病心肌病的潜在治疗方法。