AT1 signaling in cardiac hypertrophy and apoptosis

说明(申请人提供)：血管紧张素II(Ang II)的心血管效应主要通过Ang II 1型受体(AT1)信号传导。了解AT1引起心肌肥大和心力衰竭的信号机制是极其重要的。有大量证据表明，AT1通过G蛋白依赖和非依赖机制作用于表皮生长因子受体(EGFR)。因此，本研究的目的是评估这些信号机制在调控心肌肥厚和细胞凋亡中的作用。这个项目有两个具体目标。在目标1中，将确定过度表达缺乏Gaq偶联的AT1突变体的转基因小鼠是否刺激了心肌肥大，同时减少了细胞凋亡。在目标2中，将确定在过度表达不能激活EGFR的AT1突变体的转基因小鼠中，心肌肥厚是否被消除，而细胞凋亡被激活。将应用死后测量器官重量、超声心动图、左心室插管、组织学分析来表征心肌肥大、细胞凋亡和功能。免疫印迹、免疫染色、基因组和蛋白质组分析将用于揭示下游信号机制。

DESCRIPTION (provided by applicant): The cardiovascular effects of angiotensin II (Ang II) are primarily mediated via signaling through Ang II type 1 receptor (AT1). Understanding the signaling mechanisms by which AT1 causes cardiac hypertrophy and heart failure is extremely important. There is considerable evidence that AT1 acts through both G protein-dependent and -independent mechanisms and transactivates epidermal growth factor receptor (EGFR). Therefore the goal of this study is to evaluate these signaling mechanisms in modulating cardiac hypertropy and apoptosis. There are 2 specific aims of this project. In aim 1, it will be determined if cardiac hypertrophy is stimulated while apoptosis is reduced in transgenic mice overexpressing an AT1 mutant lacking Gaq coupling. In aim 2, it will be determined if cardiac hypertrophy is abolished while apoptosis is activated in transgenic mice overexpressing AT1 mutant which cannot activate EGFR. Postmortem measurements of organ weight, echocardiography, LV catheterization, histological analyses will be appllied to characterize cardiac hypertrophy, apoptosis, and function. Immunoblotting, immunostaining, genomic and proteomic analyses will be used to reveal the down stream signaling mechanisms.