Role of BMPRII Mutants in the Pathogenesis of Pulmonary Hypertension

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DESCRIPTION (provided by applicant): Pulmonary hypertension (PH) is characterized by an increase in pulmonary vascular resistance that impedes ejection of blood by the right ventricle, leading to right ventricular failure. Primary PH (PPH) is a rare but progressive disease with a mortality of 30 percent over 4 years. Recently germline mutations in bone morphogenetic protein receptor type II (BMPRII), a member of the transforming growth factor ¿ (TGF ¿) receptor family, have been found in over 50 percent of familial PPH patients and in 30 percent of sporadic cases of PPH. Mutations have been found in the extracellular, ligand binding, and cytoplasmic serine/threonine kinase domains, as well as the long carboxyl-terminal region (tail domain). The long-term objective of this application is to understand the molecular mechanism(s) by which BMPRII mutations contribute to the pathogenesis of pulmonary arterial hypertension. We found that BMPs promote, apoptotic cell death in normal human pulmonary artery smooth muscle cells (PASMCs). BMP-mediated apoptosis in PASMCs is associated with activation of caspases-3, -8, and -9, cytochrome c release, and downregulation of Bcl-2. PASMCs expressing mutant forms of BMPRII identified in PPH patients are resistant to BMP- mediated apoptosis. The specific hypothesis to be tested is that mutation(s) in the BMPRII disrupts BMP- mediated apoptosis in PASMCs, which is required for maintenance of normal cell number in the pulmonary vasculature. In Specific Aim 1, we will characterize the apoptotic-signaling pathway mediated by BMP7 in PASMCs. In Specific Aim 2, we will characterize the biological activities of BMPRII mutants found in PPH and generate transgenic mice expressing a BMPRII tail domain truncation mutant gene in smooth muscle to examine the role of this mutant BMPRII in vivo. We recently discovered that neuronal cell death-inducible putative kinase (NIPK) interacts with the tail domain of BMPRII in mammalian cells. NIPK contains a ser/thr kinase-like domain. Therefore, in Specific Aim 3 we will focus on the functional role of the interaction between NIPK and the tail domain of BMPRII in the regulation of BMP-mediated signaling pathways. These studies will elucidate the mechanism of BMP-dependent apoptosis in PASMCs and the role of the tail domain of the BMPRII in the regulation of the BMP signaling pathway, which is of fundamental importance to understanding the molecular mechanisms underlying the pathogenesis of pulmonary hypertension.