The Angiotensin II type I (AT1) receptor-associated protein, ATRAP, is a novel transmembrane protein identified as a selective partner of AT1 receptor, however the role of ATRAP on AT1 receptor function(s) has not been elucidated. Our recent in vitro studies showed that ATRAP knock down using RNAi resulted in a decrease in Akt phosphorylation and a reduction in vascular smooth muscle cell (VSMC) proliferation whereas overexpression of ATRAP by in vivo gene transfer resulted in cardiac and vascular hypertrophy. Taken together, our data suggest that ATRAP plays an important role in vascular growth. Our central hypothesis is that the biochemical interaction of ATRAP with AT1 receptor plays a critical role in the signaling activity of the receptor and is functionally important for AT1 receptor-mediated vascular actions in vivo. Accordingly, this application will focus on the mechanism of ATRAP mediated vascular growth and will examine the role of ATRAP in vascular function by the following aims:
Aim 1) To identify the molecular mechanism of ATRAP-mediated cell growth. We will examine the mechanisms of Akt downregulation by ATRAP knockdown, and its consequences on cell growth and apoptosis; we will characterize the phosphorylation of Akt and we will determine the state of activation of the immediate regulators of Akt, PI3-K and PDK1;
Aim 2) To study in vivo the consequences of deficiency in ATRAP expression on vascular function and remodeling. Based on the data in VSMCs we postulate that ATRAP will be determinant in vascular function and its loss would result in a blunting of smooth muscle cell growth, vascular contractility and vascular remodeling. Therefore, we will evaluate vessel contractility and we will use an in vivo model of vascular remodeling to assess the structural response in the vessel wall to Ang II infusion into ATRAP knockout or wild type mice. We will also characterize the consequences of ATRAP knockout on vascular hemodynamics. The studies described in this grant application will provide critical information to understand the mechanism and functional significance of AT1 receptor interaction with ATRAP and will have important implications for the development of novel therapeutic agents for cardiovascular diseases. ? ? ?
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