A1-ADRENERGIC RECEPTORS PREVENT PATHOLOGIC VENTRICULAR REMODELING FOLLOWING MI

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.