Enhanced Ca2+-sensing receptor function in pulmonary hypertension

Aya Yamamura, Hisao Yamamura, Jason X.J. Yuan

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Pulmonary arterial hypertension (PAH) is a rare, progressive, and fetal disease. The five-year survival rate after diagnosis is ~50%. In Japan, PAH is listed in the Specified Rare and Intractable Diseases. Pulmonary vascular remodeling and sustained pulmonary vasoconstriction are the major causes for the elevated pulmonary vascular resistance (PVR) in PAH. The pathogenic mechanisms involved in the pulmonary vascular abnormalities in PAH remain unclear. Sustained vasoconstriction and vascular remodeling owing to proliferation of pulmonary arterial smooth muscle cells (PASMCs) are key pathogenic events that lead to early morbidity and mortality. These events have been closely linked to Ca2++ mobilization and signaling in PASMCs. An increase in cytosolic Ca2+ concentration ([Ca2+]cyt) in PASMCs is an important stimulus for pulmonary vasoconstriction and cell proliferation which subsequently cause pulmonary vascular wall thickening followed by the increase in PVR. Increased resting [Ca2+]cyt and enhanced Ca2+ influx have been implicated in PASMCs from PAH patients, but precise therapeutic targets to interrupt these signal pathways have not been identified. We recently found that the extracellular Ca2+-sensing receptor (CaSR), a G protein-coupled receptor (GPCR), is upregulated in PASMCs from patients with idiopathic pulmonary arterial hypertension (IPAH). In addition, blockage of the CaSR with an antagonist (NPS2143) prevents the development of pulmonary hypertension and right ventricular hypertrophy in animal models of pulmonary hypertension. The functionally upregulated CaSR in PASMCs is a novel pathogenic mechanism contributing to the augmented Ca2+ signaling and excessive cell proliferation in IPAH. Targeting CaSR in PASMCs may help develop novel therapeutic approach for PAH.

Original languageEnglish (US)
Pages (from-to)1351-1359
Number of pages9
JournalYakugaku Zasshi
Volume133
Issue number12
DOIs
StatePublished - 2013
Externally publishedYes

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Keywords

  • NPS2143
  • Pulmonary artery
  • Pulmonary hypertension
  • Smooth muscle

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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