Atrial Natriuretic Peptide and Receptor Genes in Hypoxia

University Of Alabama At Birmingham, Birmingham AL

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Abstract

DESCRIPTION (provided by applicant): Hypoxic stress results in pulmonary vasoconstriction, hypertension and vascular remodeling, ultimately leading to right heart failure and death by upsetting the balance in the normal relationships between vasoconstrictor and vasodilator and between mitogenic and growth inhibiting pathways in lung. Our previous studies in rodent models have provided convincing evidence that endogenous atrial natriuretic peptide (ANP) protects against hypoxia-induced pulmonary hypertension and vascular remodeling. More recently, we have shown that transforming growth factor-beta (TGF-B) plays a dominant role in pulmonary vascular remodeling and extracellular matrix molecule (ECM) expression in response to hypoxic stress, resulting in sustained pulmonary hypertension and right ventricular hypertrophy. Our proposed research focuses on delineating the specific molecular/cellular mechanisms by which natriuretic peptide (NP)-cGMP-protein kinase G (PKG) signaling antagonizes important hypoxia-induced mitogenic/profibrogenic pathways in lung and in peripheral pulmonary arterial smooth muscle cells (PASMCs) in vitro and thus protects against pathologic pulmonary vascular remodeling/fibrosis. We will expand on the provocative preliminary observation that ANP and cGMP inhibit TGF-B-induced nuclear translocation of phosphorylated-Smad2 and 3 in PASMCs, defining for the first time a precise molecular mechanism by which ANP signaling may protect against pulmonary vascular remodeling/fibrosis in response to hypoxia i.e., by interfering with downstream signaling from TGF-B. Our proposed research will utilize state-of-the-art 2-D proteomic/Western analysis, mass spectrometric and phosphor-peptide sequencing techniques to test the novel hypothesis that ANP signaling (i.e. cGMP/PKG) interrupts the TGF-B signal transduction cascade by over-phosphorylation of Smad2 and Smad3 at sites (e.g. the linker or MH1 regions) other than the C-terminal S422/423/S425 residues that are normally phosphorylated in the course of TGF-B signaling, thus blocking nuclear translocation and binding (via complex formation with transcription factors) of pSmad2 and pSmad3 to TGF-B-Smad response elements in the promoter regions of ECM genes. Based on these novel findings, we will test two alternative/possibly complementary strategies for reversing established hypoxia-induced pulmonary hypertension/vascular remodeling, blocking TGF-B signaling and inhibiting cGMP degradation with sildenafil, using novel transgenic mouse models. Chronic pulmonary hypertension is a debilitating syndrome characterized by increased pulmonary arterial pressure with concomitant increases in pulmonary vascular remodeling/fibrosis/resistance, frequently leading to respiratory and cardiac failure. Our proposed mechanistic studies will lead to innovative and effective therapeutic approaches to this important cause of morbidity and mortality in the American population.