RGD Reference Report - Enhanced Ca(2+)-sensing receptor function in idiopathic pulmonary arterial hypertension. - Rat Genome Database

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Enhanced Ca(2+)-sensing receptor function in idiopathic pulmonary arterial hypertension.

Authors: Yamamura, A  Guo, Q  Yamamura, H  Zimnicka, AM  Pohl, NM  Smith, KA  Fernandez, RA  Zeifman, A  Makino, A  Dong, H  Yuan, JX 
Citation: Yamamura A, etal., Circ Res. 2012 Aug 3;111(4):469-81. doi: 10.1161/CIRCRESAHA.112.266361. Epub 2012 Jun 22.
RGD ID: 7205669
Pubmed: PMID:22730443   (View Abstract at PubMed)
PMCID: PMC3695473   (View Article at PubMed Central)
DOI: DOI:10.1161/CIRCRESAHA.112.266361   (Journal Full-text)

RATIONALE: A rise in cytosolic Ca(2+) concentration ([Ca(2+)](cyt)) in pulmonary arterial smooth muscle cells (PASMC) is an important stimulus for pulmonary vasoconstriction and vascular remodeling. Increased resting [Ca(2+)](cyt) and enhanced Ca(2+) influx have been implicated in PASMC from patients with idiopathic pulmonary arterial hypertension (IPAH). OBJECTIVE: We examined whether the extracellular Ca(2+)-sensing receptor (CaSR) is involved in the enhanced Ca(2+) influx and proliferation in IPAH-PASMC and whether blockade of CaSR inhibits experimental pulmonary hypertension. METHODS AND RESULTS: In normal PASMC superfused with Ca(2+)-free solution, addition of 2.2 mmol/L Ca(2+) to the perfusate had little effect on [Ca(2+)](cyt). In IPAH-PASMC, however, restoration of extracellular Ca(2+) induced a significant increase in [Ca(2+)](cyt). Extracellular application of spermine also markedly raised [Ca(2+)](cyt) in IPAH-PASMC but not in normal PASMC. The calcimimetic R568 enhanced, whereas the calcilytic NPS 2143 attenuated, the extracellular Ca(2+)-induced [Ca(2+)](cyt) rise in IPAH-PASMC. Furthermore, the protein expression level of CaSR in IPAH-PASMC was greater than in normal PASMC; knockdown of CaSR in IPAH-PASMC with siRNA attenuated the extracellular Ca(2+)-mediated [Ca(2+)](cyt) increase and inhibited IPAH-PASMC proliferation. Using animal models of pulmonary hypertension, our data showed that CaSR expression and function were both enhanced in PASMC, whereas intraperitoneal injection of the calcilytic NPS 2143 prevented the development of pulmonary hypertension and right ventricular hypertrophy in rats injected with monocrotaline and mice exposed to hypoxia. CONCLUSIONS: The extracellular Ca(2+)-induced increase in [Ca(2+)](cyt) due to upregulated CaSR is a novel pathogenic mechanism contributing to the augmented Ca(2+) influx and excessive PASMC proliferation in patients and animals with pulmonary arterial hypertension.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
pulmonary hypertension  ISOCasr (Rattus norvegicus)7205669; 7205669protein:increased expression:pulmonary artery (rat)RGD 
pulmonary hypertension  IEP 7205669protein:increased expression:pulmonary artery (rat)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Casr  (calcium-sensing receptor)

Genes (Mus musculus)
Casr  (calcium-sensing receptor)

Genes (Homo sapiens)
CASR  (calcium sensing receptor)


Additional Information