Ethanol on Excitation-Contraction in Cardiac Cells

乙醇对心肌细胞兴奋收缩的影响

• 批准号: 7856019
• 负责人: ANDREW P THOMAS
• 金额: $ 15.6万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7856019
• 关键词: Accounting; Acute; Adrenergic Agents; Affect; Alcoholic Cardiomyopathy; Alcoholism; Alcohols; Animal Feed; Animal Model; Binding; Binding Sites; Cardiac; Cardiac Myocytes; Cardiac Output; Cardiomyopathies; Cells; Chronic; Coupling; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Development; Dihydropyridines; Electrophysiology (science); Elements; Ethanol; Functional disorder; Grant; Heart; Heart Atrium; Heart Diseases; Heart failure; Human; Image; Individual; Ions; Lead; Lesion; Link; Messenger RNA; Molecular; Molecular Biology; Myocardial; Pathway interactions; Play; Precipitating Factors; Process; Property; Protein Isoforms; Proteins; Rattus; Regulation; Regulatory Element; Relative (related person); Reticulum; Role; Signal Pathway; Signal Transduction; Time; Work; adrenergic; alcohol effect; chronic alcohol ingestion; depression; dihydropyridine; feeding; indium arsenide; insight; non-alcoholic; novel; problem drinker; research study

DESCRIPTION (provided by applicant): Chronic alcoholism is a major cause of cardiomyopathy in humans and leads to a variety of changes that interfere with contractile function in the hearts of ethanol-fed animal models. Features of alcoholic cardiomyopathy include decreased cardiac output, impaired myocardial contractility and atrial dysrhythmias. There are also direct cardiodepressant effects of alcohol during acute administration. Some of the features of alcoholic heart disease may reflect adaptive changes induced by these acute ethanol actions. Our studies during the previous granting period have identified a number of targets of acute ethanol action within the excitation-contraction (E-C) coupling cascade, including sarcolemmal Na+ and Ca2+ channels, which lead to depression of the cytosolicCa2+ ([Ca2+]i) transients that drive contraction. We have also identified specific changes in E C coupling in the hearts of ethanol-fed rats, which suggest a selective lesion in the L-type Ca2+ channel and its regulation by cAMP-dependent protein kinase. In the work proposed here, we will further investigate the elements of E C coupling that are affected by acute ethanol, with a view to elucidating which of these is likely to contribute to the deficient [Ca2+]i transients. However, the principal aims of the proposed studies will be to characterize the changes in E C coupling following chronic ethanol consumption, and to determine the mechanism of these changes and how they lead to deficiencies in cardiac function. Specifically, we will investigate the following linked hypotheses: Alterations in the channel subunit isoform composition and/or expression leads to a channel that is defective, either in (1) basal channel properties, (2) coupling to intracellular Ca2+ release pathways, (3) regulation by the normal cAMP-dependent signaling pathway, and/or (4) localization within the cardiomyocyte. These experiments will utilize a combination of [Ca2+]i imaging, electrophysiology and molecular biology approaches. The proposed work will yield new insights into the changes in E C coupling that underlie cardiac dysfunction induced by chronic ethanol consumption. These findings may also have broader implications in elucidating the causal factors associated with the development of other aberrant adaptive processes in the heart, which eventually lead to cardiac failure

描述（由申请人提供）：慢性酒精中毒是人类心肌病的主要原因，并导致多种变化，干扰乙醇喂养动物模型的心脏收缩功能。酒精性心肌病的特征包括心输出量减少、心肌收缩力受损和心房心律失常。在急性给药期间，酒精也有直接的心脏抑制作用。酒精性心脏病的一些特征可能反映了这些急性乙醇作用引起的适应性变化。我们在之前的研究期间已经确定了兴奋-收缩（E-C）偶联级联中急性乙醇作用的许多靶点，包括肌上皮Na+和Ca2+通道，它们导致驱动收缩的细胞壁Ca2+ ([Ca2+]i)瞬态的抑制。我们还发现了乙醇喂养大鼠心脏中E - C偶联的特异性变化，这表明l型Ca2+通道的选择性损伤及其受camp依赖性蛋白激酶的调节。在这里提出的工作中，我们将进一步研究受急性乙醇影响的E - C偶联元素，以阐明这些元素中哪一个可能导致[Ca2+]i瞬态缺陷。然而，拟议研究的主要目的将是表征慢性乙醇消耗后E - C偶联的变化，并确定这些变化的机制以及它们如何导致心功能缺陷。具体来说，我们将研究以下相关假设：通道亚基异构体组成和/或表达的改变导致通道缺陷，要么是(1)基础通道特性，(2)与细胞内Ca2+释放途径的偶联，(3)正常camp依赖信号通路的调节，和/或(4)心肌细胞内的定位。这些实验将利用[Ca2+]i成像，电生理学和分子生物学方法的组合。提出的工作将产生新的见解，在E - C偶联的变化，潜在的心脏功能障碍引起的慢性乙醇消耗。这些发现也可能在阐明与心脏中其他异常适应过程的发展相关的因果因素方面具有更广泛的意义，这些过程最终导致心力衰竭