AT1 signaling in cardiac hypertrophy and apoptosis

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.