Rational An increase [Ca2+]cyt in pulmonary arterial smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction and a critical stimulation for PASMC proliferation and migration. We previously 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 Ca2+ influx in PASMC and the implication of CaSR in the development of PH remain elusive.
Objective To test the hypothesis that CaSR functionally interacts with TRPC6 to regulate [Ca2+]cyt in PASMC in the development of pulmonary hypertension.
Methods and Results Downregulation of CaSR or TRPC6 with siRNA inhibited Ca2+-induced [Ca2+]cyt increase in IPAH-PASMC (in which CaSR is upregulated), while overexpression of CaSR or TRPC6 enhanced Ca2+-induced [Ca2+]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, while 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.
Conclusions 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.
Keywords G protein-coupled receptor; ionic ligand; hypoxia-induced pulmonary hypertension.
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