The goal of our research is to elucidate the role of atrial natriuretic pep de (ANP) and ANP receptors in hypoxia-induced pulmonary hypertension. The gen al hypothesis of the current proposal is that ANP gene expression is enhanced, nd ANP clearance receptor (ANP-CR) gene expression in lung is suppressed, by exposure to hypoxia and that ANP has a protective effect against the develo ent of hypoxic pulmonary hypertension. Our studies during the first five years f this project have shown that ANP gene expression and ANP secretion in card c myocytes in culture, as well as the sensitivity of the pulmonary vasculatur to both endogenous and exogenous ANP in hypoxia-adapted rats are enhanced duri hypoxic exposure. We have also demonstrated that ANP-CR gene expression is suppressed in lung of hypoxia adapted rats and in cultured human pulmonary arterial smooth muscle cells during hypoxic exposure. These data define a le for ANP as a modulator hormone that protects against acute hypoxic pulmonar vasoconstriction and chronic hypoxic pulmonary hypertension. Studies descr ed in the current application will focus on cellular and molecular mechanisms the hypoxia induced alterations of ANP and ANP receptor gene expression. Speci c Aims are: 1) To determine the molecular and cellular mechanism(s) of hypox - induced ANP gene expression in cultured atrial myocytes. We will define an characteristics the cis-regulatory element(s) and transacting factors invol d in amplifying transcription of the ANP gene in atrial myocytes in response hypoxia. 2) To determine the cellular basis of selectivity of the hypoxic response of the ANP-CR gene for lung. 3) To determine the molecular and ce ular mechanism(s) of hypoxia-induced down regulation of ANP-CR gene expression i lung. Atrial myocytes transfected with fragments of ANP genomic DNA contai ng putative hypoxia response element will be studied in Specific Aim 1. Sprag - Dawley rats exposed to normobaric hypoxia (10% O2 at 1 atm) will be studied n Specific Aim 2. Vascular smooth muscle cells derived from human pulmonary tery and aorta will be studied in Specific Aim 2 and 3.
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