title: Pathogenic role of calcium-sensing receptors in the development and progression of pulmonary hypertension.
abstract: 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.
authors.affiliation: Department of Medicine, Division of Translational and Regenerative Medicine.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Tang
authors.affiliation: Kinjo Gakuin University School of Pharmacy, Nagoya, Japan;
authors.forename: Aya
authors.initials: A
authors.lastname: Yamamura
authors.affiliation: Nagoya City University Graduate School of Pharmaceutical Sciences, Nagoya, Japan; and.
authors.forename: Hisao
authors.initials: H
authors.lastname: Yamamura
authors.affiliation: Department of Medicine, Division of Translational and Regenerative Medicine.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Song
authors.affiliation: Departments of Medicine and Pharmacology, University of Illinois at Chicago, Chicago, Illinois;
authors.forename: Dustin R
authors.initials: DR
authors.lastname: Fraidenburg
authors.affiliation: Departments of Medicine and Pharmacology, University of Illinois at Chicago, Chicago, Illinois;
authors.forename: Jiwang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Medicine, Division of Translational and Regenerative Medicine.
authors.forename: Yali
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Departments of Medicine and Pharmacology, University of Illinois at Chicago, Chicago, Illinois;
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Pohl
authors.affiliation: Department of Medicine, Division of Translational and Regenerative Medicine.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Division of Translational and Regenerative Medicine.
authors.forename: Laura
authors.initials: L
authors.lastname: Jiménez-Pérez
authors.affiliation: Department of Medicine, Division of Translational and Regenerative Medicine.
authors.forename: Ramon J
authors.initials: RJ
authors.lastname: Ayon
authors.affiliation: Department of Medicine, Division of Translational and Regenerative Medicine.
authors.forename: Ankit A
authors.initials: AA
authors.lastname: Desai
authors.affiliation: Department of Medicine and Physiology, Royal Victoria Hospital, Montreal, Quebec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Goltzman
authors.affiliation: Department of Medicine, Division of Translational and Regenerative Medicine.
authors.forename: Franz
authors.initials: F
authors.lastname: Rischard
authors.affiliation: Department of Surgery, University of Arizona College of Medicine, Tucson, Arizona;
authors.forename: Zain
authors.initials: Z
authors.lastname: Khalpey
authors.affiliation: Department of Medicine, Division of Translational and Regenerative Medicine, Department of Physiology, and.
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Black
authors.affiliation: Department of Medicine, Division of Translational and Regenerative Medicine.
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
authors.affiliation: Department of Medicine, Division of Translational and Regenerative Medicine, Department of Physiology, and.
authors.forename: Ayako
authors.initials: A
authors.lastname: Makino
authors.affiliation: Department of Medicine, Division of Translational and Regenerative Medicine, Department of Physiology, and jasonyuan@email.arizona.edu.
authors.forename: Jason X J
authors.initials: JX
authors.lastname: Yuan
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D015687:Cell Hypoxia; D002465:Cell Movement; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000098:blood supply / Q000473:pathology; D008297:Male; D008564:Membrane Potentials; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011651:Pulmonary Artery / Q000473:pathology / Q000503:physiopathology; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D050052:TRPC Cation Channels / Q000502:physiology*; D000074287:TRPC6 Cation Channel; D066253:Vascular Remodeling; D014661:Vasoconstriction
chemical_list: C577923:CASR protein, mouse; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse
keywords: G protein-coupled receptor; hypoxia-induced pulmonary hypertension; ionic ligand