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


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.
Kinjo Gakuin University School of Pharmacy, Nagoya, Japan.
Aya
A
Yamamura
Qiang
Q
Guo
Hisao
H
Yamamura
Adriana M
AM
Zimnicka
Nicole M
NM
Pohl
Kimberly A
KA
Smith
Ruby A
RA
Fernandez
Amy
A
Zeifman
Ayako
A
Makino
Hui
H
Dong
Jason X-J
JX
Yuan
D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D057966:Calcimimetic Agents / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D065627:Familial Primary Pulmonary Hypertension; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D000860:Hypoxia / Q000150:complications / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016686:Monocrotaline; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009281:Naphthalenes / Q000494:pharmacology; D010627:Phenethylamines; D011437:Propylamines; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013096:Spermine / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014661:Vasoconstriction / Q000187:drug effects
D000814:Aniline Compounds; C095550:CASR protein, human; D057966:Calcimimetic Agents; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; C436740:N-(2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl)-1,1-dimethyl-2-(2-nephthyl)ethylamine; D009281:Naphthalenes; D010627:Phenethylamines; D011437:Propylamines; D044169:Receptors, Calcium-Sensing; C473605:extracellular calcium cation-sensing receptor, rat; D013096:Spermine; D016686:Monocrotaline