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

Haiyang Tang, Aya Yamamura, Hisao Yamamura, Shanshan Song, Dustin R. Fraidenburg, Jiwang Chen, Yali Gu, Nicole M. Pohl, Tong Zhou, Laura Jiménez-Pérez, Ramon J. Ayon, Ankit A. Desai, David Goltzman, Franz Rischard, Zain Khalpey, Stephan M. Black, Joe G N Garcia, Ayako Makino, Jason X J Yuan

Research output: Contribution to journalArticle

26 Citations (Scopus)

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 hypoxiainduced 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.

Original languageEnglish (US)
Pages (from-to)L846-L859
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume310
Issue number9
DOIs
StatePublished - Mar 1 2016
Externally publishedYes

Fingerprint

Calcium-Sensing Receptors
Pulmonary Hypertension
Smooth Muscle Myocytes
Lung
Vasoconstriction
Small Interfering RNA
Down-Regulation
Cell Proliferation
MicroRNAs

Keywords

  • G protein-coupled receptor
  • Hypoxia-induced pulmonary hypertension
  • Ionic ligand

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

Pathogenic role of calcium-sensing receptors in the development and progression of pulmonary hypertension. / Tang, Haiyang; Yamamura, Aya; Yamamura, Hisao; Song, Shanshan; Fraidenburg, Dustin R.; Chen, Jiwang; Gu, Yali; Pohl, Nicole M.; Zhou, Tong; Jiménez-Pérez, Laura; Ayon, Ramon J.; Desai, Ankit A.; Goltzman, David; Rischard, Franz; Khalpey, Zain; Black, Stephan M.; Garcia, Joe G N; Makino, Ayako; Yuan, Jason X J.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 310, No. 9, 01.03.2016, p. L846-L859.

Research output: Contribution to journalArticle

Tang, 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 2016, 'Pathogenic role of calcium-sensing receptors in the development and progression of pulmonary hypertension', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 310, no. 9, pp. L846-L859. https://doi.org/10.1152/ajplung.00050.2016
Tang, Haiyang ; Yamamura, Aya ; Yamamura, Hisao ; Song, Shanshan ; Fraidenburg, Dustin R. ; Chen, Jiwang ; Gu, Yali ; Pohl, Nicole M. ; Zhou, Tong ; Jiménez-Pérez, Laura ; Ayon, Ramon J. ; Desai, Ankit A. ; Goltzman, David ; Rischard, Franz ; Khalpey, Zain ; Black, Stephan M. ; Garcia, Joe G N ; Makino, Ayako ; Yuan, Jason X J. / Pathogenic role of calcium-sensing receptors in the development and progression of pulmonary hypertension. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2016 ; Vol. 310, No. 9. pp. L846-L859.
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AU - Chen, Jiwang

AU - Gu, Yali

AU - Pohl, Nicole M.

AU - Zhou, Tong

AU - Jiménez-Pérez, Laura

AU - Ayon, Ramon J.

AU - Desai, Ankit A.

AU - Goltzman, David

AU - Rischard, Franz

AU - Khalpey, Zain

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