A1-ADRENERGIC RECEPTORS PREVENT PATHOLOGIC VENTRICULAR REMODELING FOLLOWING MI

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本研究的目的是确定α 1A-肾上腺素能受体（α 1A-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时病理性心室重构是由于交感神经活动和儿茶酚胺释放增加所致。此外，增加的去甲肾上腺素水平与心力衰竭相关，预测疾病严重程度和死亡率，从而为成功使用α-AR拮抗剂或α-阻断剂治疗心力衰竭提供基础。然而，儿茶酚胺也激活a1-AR，在两项临床试验中，V-HeFT和ALLHAT，a1-阻滞剂增加了死亡率和心力衰竭。虽然心肌细胞表达a1 A和a1 B亚型，但我们实验室和其他人的工作表明，只有a1 A亚型具有保护作用。然而，目前还不清楚在病理环境中激活a1 A亚型是否会预防心力衰竭并提高生存率。本项目将检验a1 A亚型通过防止心肌细胞死亡和诱导正性肌力反应来保护心脏免受心肌梗死后病理性心室重构的假设。为了验证这一假设，目的1将检查心脏特异性α 1A转基因小鼠冠状动脉闭塞后的心室重塑。目的2将在培养的心肌细胞中检测a1 A亚型介导的缺氧应答的存活信号，以及ERK在缺氧应答的a1存活信号中的作用，无论是在培养的心肌细胞中还是在体内。目的3将检查冠状动脉闭塞后从a1 A转基因小鼠中分离的肌细胞的收缩功能，以及a1 A亚型是否防止培养的肌细胞对缺氧反应的收缩功能障碍。

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.