Aging impairments in angiotensin type 1 receptor actions

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 DESCRIPTION (provided by applicant): The overall goal of this R21 proposal is to investigate the role of the PEP7 encoded short open reading frame in age-associated changes in AT1aR action in vascular smooth muscle cells. We will test the hypothesis that age-associated dysregulation of AT1aR densities contributes to vascular smooth muscle cell senescence in part through dysregulation of AT1aR splice variants, which leads to dysregulation of AT1aR internalization and signaling. To test this hypothesis, in Aim 1, we will determine the effect of aging on AT1aR transcript expression (E1,2,3 and E1,3), AT1R binding, rate of receptor internalization, AT1R signaling pathways and cell proliferation in vascular smooth muscle cells isolated from young (4 month old) and old (32 month old) Fischer rats. We will also use RNA interference to selectively inhibit expression of the E1,2,3-AT1aR transcript in vascular smooth muscle cells isolated from these young and old rats and determine the effect on AT1R binding, internalization, signaling and cell proliferation. In Aim 2, we will compare these same parameters in a disorder of vascular remodeling to investigate the role of PEP7 in normal and abnormal aging.