Pathological function of Ca2+-sensing receptor in pulmonary arterial hypertension.
Pulmonary arterial hypertension (PAH) is defined as an intractable disease characterized by a progressive elevation of pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP), leading to right heart failure and premature death. The five-year survival rate after diagnosis is approximately 57%. Although extensive research has identified some factors associated with the cause of PAH, the etiology and pathogenesis remain unclear. In addition to Ca(2+) channel blockers (nifedipine, diltiazem), three categories of drug have been developed for the treatment of PAH based on the pathological mechanisms: prostacyclin and its analogues (epoprostenol, treprostinil, iloprost), endothelin receptor antagonists (bosentan, ambrisentan), and phosphodiesterase type 5 inhibitors (sildenafil, tadalafil). However, screening of novel types of drug acting on the signal pathway associated with the pathological mechanism underlying PAH is ongoing. We recently found that the extracellular Ca(2+)-sensing receptor (CaSR), which belongs to family C of the G protein-coupled receptor (GPCR) superfamily, is upregulated in pulmonary arterial smooth muscle cells (PASMCs) from patients with idiopathic PAH (IPAH). The upregulated CaSR is necessary for the enhanced Ca(2+) signaling and the augmented cell proliferation in PASMCs from IPAH patients. Most importantly, blockage of CaSR with an antagonist, NPS2143, prevents the development of pulmonary hypertension and right ventricular hypertrophy in animal models of pulmonary hypertension. The use of calcilytics, antagonists of CaSR, may be a novel therapeutic approach for PAH patients.
School of Pharmacy, Kinjo Gakuin University, Japan.
Aya
A
Yamamura
D000818:Animals; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation; D004195:Disease Models, Animal; D015195:Drug Design; D065627:Familial Primary Pulmonary Hypertension; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D058990:Molecular Targeted Therapy; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use; D011651:Pulmonary Artery / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation; D014661:Vasoconstriction
C436740:N-(2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl)-1,1-dimethyl-2-(2-nephthyl)ethylamine; D009281:Naphthalenes; D044169:Receptors, Calcium-Sensing; D002118:Calcium