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Calcium‐sensing Receptor, Coupled with Transient Receptor Potential Canonical Channels 6, Regulates Cytosolic [Ca 2+ ] in the Development and Progression of Pulmonary Hypertension
Author(s) -
TANG HAIYANG,
Yamamura Aya,
Fraidenburg Dustin R,
Song Shanshan,
Yamamura Hisao,
Chen Jiwang,
Gu Yali,
Ayon Ramon J,
Black Stephan M,
Garcia Joe G.N.,
Makino Ayako,
Yuan Jason X.J.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.774.11
Subject(s) - trpc6 , right ventricular hypertrophy , hypoxic pulmonary vasoconstriction , calcium sensing receptor , pulmonary hypertension , trpc , trpc1 , medicine , pulmonary artery , endocrinology , vasoconstriction , hypoxia (environmental) , lung , transient receptor potential channel , vascular resistance , muscle hypertrophy , cardiology , ventricle , receptor , chemistry , calcium , hemodynamics , calcium metabolism , oxygen , organic chemistry
Rationale Elevated pulmonary arterial pressure (PAP) in patients with pulmonary arterial hypertension (PAH) is mainly caused by increased pulmonary vascular resistance (PVR), due primarily to sustained pulmonary vasoconstriction and excessive pulmonary vascular remodeling. An increase in cytosolic free Ca 2+ concentration ([Ca 2+ ] cyt ) in pulmonary arterial smooth muscle cells (PASMCs) is not only a major trigger for pulmonary vasoconstriction but also an important stimulus for pulmonary vascular remodeling. Our previous data showed that the extracellular calcium sensing receptor (CaSR) expression and function were both enhanced in PASMC from idiopathic PAH patients. However, the implication of CaSR in the development of PAH remains elusive. Methods Casr double knockout mice ( Casr − / − Pth − / − ) and transient receptor potential canonical Channels 6 ( Trpc6 − / − ) have been exposed to hypoxia for 4 weeks to develop pulmonary hypertension. Following hypoxic exposure, right ventricle systolic pressures (RVSP), right ventricular hypertrophy by RV/(LV+S) ratios, and small pulmonary artery smooth muscle layer thickness were measured. The PAP was measured using the isolated perfused/ventilated mouse lung system. PASMCs were isolated from patients with IPAH, followed with [Ca 2+ ] cyt measurement, proliferation and migration assays. Results In the current study, we found blockade of TRPC6 channels significantly inhibits Ca 2+ ‐induced increase in [Ca 2+ ] cyt and OAG caused a larger increase in [Ca2+] cyt in IPAH PASMCs. Overexpression of CaSR and TRPC6 channels increase the extracellular Ca 2+ ‐induced [Ca 2+ ] cyt in normal PASMCs. C ompared to wild mice, both Casr − / − Pth − / − and Trpc6 − / − mice had significantly lower RVSP, less right ventricular hypertrophy, and displayed less pulmonary vascular remodeling after exposure to hypoxia. Deletion of Casr or Trpc6 gene significantly attenuates acute hypoxic vasoconstriction. Conclusions These data indicate that CaSR functionally interacts with TRPC6 and regulate [Ca 2+ ] cyt in IPAH‐PASMC. Deletions of CaSR or TRPC6 prevent the development of hypoxia‐induced PAH in mice via its modulation of extracellular Ca 2+ entry in PASMC, suggesting that CaSR may be a novel therapeutic candidate for the treatment of PAH.