Host: The 92nd Annual Meeting of the Japanese Pharmacological Society
Name : The 92nd Annual Meeting of the Japanese Pharmacological Society
Number : 92
Location : Osaka
Date : March 14, 2019 - March 16, 2019
Idiopathic pulmonary arterial hypertension (IPAH) is a rare and progressive disease of unknown pathogenesis. We previously reported that the Ca2+-sensing receptor (CaSR) is upregulated in pulmonary arterial smooth muscle cells (PASMCs) from patients with IPAH, contributing to an enhanced Ca2+ response and excessive cell proliferation in IPAH-PASMCs. However, the mechanisms underlying the upregulation of CaSR in IPAH-PASMCs have not yet been elucidated. The present results demonstrated that platelet-derived growth factor (PDGF) and its signaling pathway promote the expression of CaSR in PASMCs, thereby facilitating Ca2+ responses, cell proliferation, and migration followed by pulmonary vascular remodeling. Therefore, siRNA knockdown of PDGFα/β receptors and STAT1/3 or imatinib (a tyrosine kinase inhibitor including PDGF receptors) blocked the CaSR upregulation and functions in IPAH-PASMCs. The combination of NPS2143 (a CaSR antagonist) and imatinib acted additively to inhibit the development of pulmonary hypertension in monocrotaline-treated rats. In conclusion, the crosslink between CaSR and PDGF signals is a novel pathophysiological mechanism contributing to the development of IPAH.
