CHRONIC HYPOXIA AND RESISTANCE TO MYOCARDIAL ISCHEMIA

慢性缺氧和抗心肌缺血

• 批准号: 6621701
• 负责人: JOHN E BAKER
• 金额: $ 26.25万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6621701
• 关键词: adenosine triphosphate; biological signal transduction; congenital heart disorder; cyclic GMP; enzyme activity; fluorescence microscopy; gene expression; heart function; heat shock proteins; human tissue; immature animal; immunofluorescence technique; immunoprecipitation; infant human (0-1 year); laboratory rabbit; mitogen activated protein kinase; myocardial ischemia /hypoxia; myocardium; nitric oxide; nitric oxide synthase; phosphorylation; potassium channel; protein kinase C; recombinant virus; reperfusion; western blottings

The overall objective of this proposal is to improve cardioprotection in children undergoing surgery for repair of congenital heart defects. The majority of infants undergoing cardiac surgery exhibit varying degrees of cyanotic heart disease where the myocardium is chronically perfused with hypoxic blood. To investigate mechanisms of adaptation to chronic hypoxia and resistance to myocardial ischemia a non-surgical rabbit model of chronic hypoxia from birth has been developed. The relationship between protein kinases and nitric oxide synthase and whether they activate sarcolemmal or mitochondrial K/ATP channels to confer cardioprotection in chronically hypoxic hearts is unknown. We hypothesize that chronic hypoxia activates protein kinase signal transduction pathways leading to activation of nitric oxide synthase which confers cardioprotection by activation of sarcolemmal and mitochondrial K/ATP channels. We propose to test this hypothesis in isolated hearts and isolated myocytes from rabbits raised from birth in hypoxic and normoxic environments and in right atrial tissue from cyanotic and acyanotic infants undergoing surgical repair of congenital heart defects. We shall determine (1) whether protein kinases participate in the mechanism of adaptation to chronic hypoxia and resistance to ischemia in isolated hearts from normoxic and chronically hypoxic immature rabbits and in human hearts from infants with cyanotic and acyanotic heart defect, (2) the mechanisms by which chronic hypoxia controls nitric oxide production from nitric oxide synthase and resistance to subsequent ischemia and (3) the mechanisms by which protein kinases and nitric oxide synthase mediate the activity of the sarcolemmal and mitochondrial K/ATP channels and the involvement of cyclic GMP in controlling resistance to myocardial ischemia induced by chronic hypoxia. The findings from these studies should enhance our understanding of the cardioprotective mechanisms resulting from adaptation to chronic hypoxia in the immature heart and may lead to the development of new strategies to protect hearts of children undergoing surgical repair for congenital birth defects.

本建议的总体目标是改善先天性心脏缺陷手术修复儿童的心脏保护。大多数接受心脏手术的婴儿表现出不同程度的青紫性心脏病，其中心肌长期灌注低氧血液。为了探讨兔对慢性缺氧的适应机制和对心肌缺血的抵抗，我们建立了兔出生时慢性缺氧的非手术模型。蛋白激酶和一氧化氮合酶之间的关系以及它们是否激活肌层或线粒体K/ATP通道以赋予慢性缺氧心脏保护作用尚不清楚。我们假设慢性缺氧激活蛋白激酶信号转导通路，导致一氧化氮合酶的激活，一氧化氮合酶通过激活肌层和线粒体K/ATP通道赋予心脏保护作用。我们建议在缺氧和常氧环境下出生的兔子的离体心脏和离体肌细胞以及接受先天性心脏缺陷手术修复的青紫和无紫婴儿的右心房组织中验证这一假设。我们将确定(1)蛋白激酶是否参与正常缺氧和慢性缺氧幼兔离体心脏和紫绀型和无绀型心脏缺陷婴儿心脏适应慢性缺氧和抵抗缺血的机制；(2)慢性缺氧控制一氧化氮合酶产生一氧化氮和对缺血抵抗的机制；(3)蛋白激酶和一氧化氮合酶介导肌层和线粒体K/ATP通道活性的机制以及环GMP参与控制慢性缺氧引起的心肌缺血抵抗的机制。这些研究的发现将增强我们对未成熟心脏对慢性缺氧的适应所导致的心脏保护机制的理解，并可能导致开发新的策略来保护接受先天性先天性缺陷手术修复的儿童的心脏。