Pathological function of Ca2+-sensing receptor in pulmonary arterial hypertension

Abstract

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.

Fig. 1.

Chemical structures of drugs for pulmonary arterial hypertension. In addition to Ca²⁺ channel blockers (A), prostacyclin and its analogues (B), endothelin receptor antagonists (C), and phosphodiesterase type 5 (PDE5) inhibitors (D) are now widely used for the treatment of pulmonary arterial hypertension (PAH).

Fig. 2.

Enhanced Ca²⁺-sensing receptor function in idiopathic pulmonary arterial hypertension. (A) Representative traces of [Ca²⁺]_cyt changes in response to extracellular application of 0.1, 0.5, 1.1, 2.2, and 10 mM Ca²⁺ and the dose response curves in pulmonary arterial smooth muscle cells (PASMCs) from normal subjects and patients with idiopathic pulmonary arterial hypertension (IPAH) (n=57∼183 cells). The EC₅₀ for extracellular Ca²⁺-induced [Ca²⁺]_cyt increase in IPAH-PASMCs is 1.22 mM. (B) Western blot analysis on Ca²⁺-sensing receptor (CaSR) in membrane proteins isolated from PASMCs and lung tissues of normal subjects (Nor) and IPAH patients. The CaSR protein levels were normalized to the β-tubulin level. [modified from ref. 12].

Fig. 3.

Phylogenetic tree of family C of G-protein-coupled receptors. The Ca²⁺-sensing receptor (CaSR, also known as GPRC2A) belongs to family C of the G protein-coupled receptor (GPCR) superfamily, which includes the metabotropic glutamate receptors (mGluRs), GABA_B receptors, and taste receptors, as well as orphan receptors. The structure of CaSR consists of a large N-terminal extracellular domain, a central core with seven transmembrane domains, and an intracellular C-terminal tail. [adapted from refs. and 15].

Fig. 4.

Chemical structures of modulators for Ca²⁺-sensing receptor. (A) The chemical structure of calcimimetics, or positive allosteric modulators, NPS R467, tecalcet (also known as NPS R568), cinacalcet (NPS1493, AMG073), and calindol. Tecalcet was developed for primary/secondary hyperthyroidism but dropped during clinical trials. Cinacalcet is used for uremic secondary hyperparathyroidism. (B) The chemical structure of calcilytics, or negative allosteric modulators, NPS2143, Calhex 231, SB-423562 (NPSP795), and SB-423557 (NPSP790). SB-423562 and SB-423557, an orally bioavailable precursor for SB-423562, are currently in clinical trials for osteoporosis.

Fig. 5.

A calcilytic, NPS2143, rescues development of pulmonary hypertension. (A) Representative records of right ventricular pressure (RVP) in control and monocrotaline-induced pulmonary hypertensive (MCT) rats treated with vehicle or NPS2143. (B) Representative hematoxylin and eosin (H&E) images of small pulmonary arteries in control and MCT rats treated with vehicle or NPS2143. The magnified images of area surrounded by a black border in upper panels are shown in lower panels. [modified from ref. 12].