A1-ADRENERGIC RECEPTORS PREVENT PATHOLOGIC VENTRICULAR REMODELING FOLLOWING MI

A1 肾上腺素能受体可预防 MI 后的病理性心室重构

• 批准号: 8360552
• 负责人: Timothy D O'Connell
• 金额: $ 33.61万
• 依托单位: SANFORD RESEARCH/USD
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360552
• 关键词: Adrenergic Receptor; Cardiac; Cardiac Myocytes; Cardiovascular system; Catecholamines; Cessation of life; Clinical Trials; Coronary artery; Foundations; Functional disorder; Funding; Goals; Grant; Heart; Heart failure; Hypoxia; Mediating; Muscle Cells; Myocardial Infarction; National Center for Research Resources; Norepinephrine; Pathologic; Principal Investigator; Research; Research Infrastructure; Resources; Role; Severity of illness; Signal Transduction; Source; Testing; Transgenic Mice; United States National Institutes of Health; Ventricular Remodeling; Work; artery occlusion; cost; improved; in vivo; mortality; prevent; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The goal of this study is to define a protective role of the a1A-adrenergic receptor (a1A-AR) in ventricular remodeling following myocardial infarction. The neurohormonal hypothesis suggests that pathologic ventricular remodeling in heart failure is due to increased sympathetic activity and catecholamine release. Moreover, increased norepinephrine levels correlate with heart failure, predicting disease severity and mortality, thereby providing the foundation for the successful use of a-AR antagonists, or a-blockers, to treat heart failure. However, catecholamines also activate a1-ARs, and in two clinical trials, V-HeFT and ALLHAT, a1-blockers increased mortality and heart failure. Although the cardiac myocytes expresses both the a1A- and a1B-subtypes, work from our lab and others suggest that only the a1A-subtype is protective. However, it is unknown whether activation of the a1A-subtype in a pathological setting will prevent heart failure and improve survival. This project will test the hypothesis that the a1A-subtype protects the heart from pathologic ventricular remodeling following myocardial infarction by preventing myocyte death and inducing positive inotropic responses. To test this hypothesis Aim 1 will examine ventricular remodeling following coronary artery occlusion in cardiac-specific a1A-transgenic mice. Aim 2 will examine a1A-subtype mediated survival signaling in response to hypoxia in cultured myocytes, as well as the role of ERK in a1-survival signaling in response to hypoxia, both in cultured myocytes and in vivo. Aim 3 will examine contractile function in myocytes isolated from a1A-transgenic mice following coronary artery occlusion and if the a1A-subtype prevents contractile dysfunction in response to hypoxia in cultured myocytes.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 本研究的目的是明确A1a-肾上腺素能受体(A1a-AR)在心肌梗死后心室重构中的保护作用。神经激素假说认为，心力衰竭的病理性心室重构是由于交感神经活性增加和儿茶酚胺释放所致。此外，去甲肾上腺素水平的增加与心力衰竭相关，可以预测疾病的严重程度和死亡率，从而为成功使用a-AR拮抗剂或a-受体阻滞剂治疗心力衰竭奠定了基础。然而，儿茶酚胺也激活A1-AR，在V-HeFT和ALLHAT两项临床试验中，A1-阻滞剂增加了死亡率和心力衰竭。虽然心肌细胞同时表达A1a和A1B亚型，但我们和其他实验室的工作表明，只有A1a亚型具有保护作用。然而，目前尚不清楚在病理环境下激活A1a亚型是否会预防心力衰竭并提高存活率。该项目将验证这样的假设，即A1a亚型通过防止心肌细胞死亡和诱导正性变力反应来保护心脏免受心肌梗死后病理性心室重构的影响。为了验证这一假设，目标1将在心脏特异的A1a转基因小鼠中检测冠状动脉闭塞后的心室重构。目的2研究A1a亚型介导的心肌细胞缺氧反应生存信号，以及ERK在培养心肌细胞和在体缺氧反应A1生存信号中的作用。目的3将检测A1a转基因小鼠冠状动脉闭塞后分离的心肌细胞的收缩功能，以及A1a亚型是否能防止培养的心肌细胞因缺氧而出现收缩功能障碍。