Pathogenic role of calcium-sensing receptors in the development and progression of pulmonary hypertension.

TitlePathogenic role of calcium-sensing receptors in the development and progression of pulmonary hypertension.
Publication TypeJournal Article
Year of Publication2016
AuthorsTang H, Yamamura A, Yamamura H, Song S, Fraidenburg DR, Chen J, Gu Y, Pohl NM, Zhou T, Jiménez-Pérez L, Ayon RJ, Desai AA, Goltzman D, Rischard F, Khalpey Z, Black SM, Garcia JGN, Makino A, Yuan JXJ
JournalAm J Physiol Lung Cell Mol Physiol
Volume310
Issue9
PaginationL846-59
Date Published2016 May 01
ISSN Number1522-1504
KeywordsAnimals, Calcium Signaling, Cell Hypoxia, Cell Movement, Cells, Cultured, HEK293 Cells, Humans, Hypertension, Pulmonary, Lung, Male, Membrane Potentials, Mice, Inbred C57BL, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Pulmonary Artery, Receptors, G-Protein-Coupled, TRPC Cation Channels, Vascular Remodeling, Vasoconstriction
Abstract

<p>An increase in cytosolic free Ca(2+) concentration ([Ca(2+)]cyt) in pulmonary arterial smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction and a critical stimulation for PASMC proliferation and migration. Previously, we demonstrated that expression and function of calcium sensing receptors (CaSR) in PASMC from patients with idiopathic pulmonary arterial hypertension (IPAH) and animals with experimental pulmonary hypertension (PH) were greater than in PASMC from normal subjects and control animals. However, the mechanisms by which CaSR triggers Ca(2+) influx in PASMC and the implication of CaSR in the development of PH remain elusive. Here, we report that CaSR functionally interacts with TRPC6 to regulate [Ca(2+)]cyt in PASMC. Downregulation of CaSR or TRPC6 with siRNA inhibited Ca(2+)-induced [Ca(2+)]cyt increase in IPAH-PASMC (in which CaSR is upregulated), whereas overexpression of CaSR or TRPC6 enhanced Ca(2+)-induced [Ca(2+)]cyt increase in normal PASMC (in which CaSR expression level is low). The upregulated CaSR in IPAH-PASMC was also associated with enhanced Akt phosphorylation, whereas blockade of CaSR in IPAH-PASMC attenuated cell proliferation. In in vivo experiments, deletion of the CaSR gene in mice (casr(-/-)) significantly inhibited the development and progression of experimental PH and markedly attenuated acute hypoxia-induced pulmonary vasoconstriction. These data indicate that functional interaction of upregulated CaSR and upregulated TRPC6 in PASMC from IPAH patients and animals with experimental PH may play an important role in the development and progression of sustained pulmonary vasoconstriction and pulmonary vascular remodeling. Blockade or downregulation of CaSR and/or TRPC6 with siRNA or miRNA may be a novel therapeutic strategy to develop new drugs for patients with pulmonary arterial hypertension.</p>

DOI10.1152/ajplung.00050.2016
Alternate JournalAm. J. Physiol. Lung Cell Mol. Physiol.
PubMed ID26968768
PubMed Central IDPMC4867349
Grant ListR01 HL060190 / HL / NHLBI NIH HHS / United States
R01 HL066012 / HL / NHLBI NIH HHS / United States
R01 HL115014 / HL / NHLBI NIH HHS / United States