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The Functional Coupling of CaSR and TRPC6 Contributes to Enhanced Proliferation in Pulmonary Arterial Smooth Muscle Cells
Author(s) -
Fernandez Ruby,
JimenezPerez Laura,
Song Shanshan,
Tang Haiyang,
Yuan Jason
Publication year - 2015
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.29.1_supplement.662.15
Subject(s) - trpc6 , downregulation and upregulation , hypoxic pulmonary vasoconstriction , extracellular , calcium sensing receptor , trpc , pulmonary hypertension , medicine , endocrinology , receptor , chemistry , transient receptor potential channel , microbiology and biotechnology , biology , calcium , biochemistry , calcium metabolism , gene
An increase in cytosolic free Ca 2+ ([Ca 2+ ] cyt ) in pulmonary arterial smooth muscle cells (PASMC) is not only a major trigger for pulmonary vasoconstriction but also an important stimulus for PASMC proliferation.We have previously shown both extracellular Ca 2+ ‐sensing receptor (CaSR), a G protein‐coupled receptor, and TRPC6, a transient receptor potential cation channel, are upregulated in PASMC from idiopathic pulmonary arterial hypertension (IPAH) patients. Furthermore, extracellular Ca 2+‐ induced increase in [Ca 2+ ] cyt was enhanced in PASMC from patients with idiopathic pulmonary arterial hypertension (IPAH) compared to normal patients. However, the implication of increased CaSR and TRPC6 in pulmonary hypertension remains unknown. In this study, our data show the inhibition of CaSR by siRNA significantly inhibited hypoxia‐induced proliferation in both normal and IPAH PASMC. Furthermore, IPAH‐PASMC treated with siRNA targeting CaSR or TRPC6 inhibited Ca 2+ ‐induced Ca 2+ entry, suggesting functional coupling of CaSR and TRPC6. In addition, PDGF‐induced proliferation in IPAH‐PASMC was inhibited by blocking either CaSR or TRCP6 via inhibitors NPS2143 and 2‐APB, respectfully, while NPS2143 was unable to block PDGF‐induced proliferation in normal PASMC. The data from this study indicate that upregulation of CaSR is functionally coupled to TRPC6 channels to increase [Ca 2+ ] cyt ; the enhanced extracellular Ca 2+ ‐induced increase in [Ca 2+ ] cyt due to upregulation of CaSR and TRPC6 plays an important role in PASMC proliferation. This suggests that CaSR could be a novel therapeutic candidate for the treatment of PH.