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1 Department of Medicine, University of California, San Diego, La Jolla, California, United States
* To whom correspondence should be addressed. E-mail: xiyuan{at}ucsd.edu.
A rise in cytosolic Ca2+ ([Ca2+]cyt) in pulmonary artery smooth muscle cells (PASMC) triggers pulmonary vasoconstriction and stimulates PASMC proliferation. The resting [Ca2+]cyt and Ca2+ entry are both increased in PASMC from patients with idiopathic pulmonary arterial hypertension (IPAH), which is believed to be a critical mechanism for sustained pulmonary vasoconstriction and excessive pulmonary vascular remodeling in these patients. Here we report that protein expression of NCX1, an NCX family member of Na+/Ca2+ exchanger proteins is upregulated in PASMC from IPAH patients compared with PASMC from normal subjects and patients with other cardiopulmonary diseases. The NCX exchanger operates in a forward (Ca2+ exit) and reverse (Ca2+ entry) mode. By activating the reverse mode of NCX, removal of extracellular Na+ caused a rapid increase in [Ca2+]cyt, which was significantly enhanced in IPAH PASMC compared with normal PASMC. Furthermore, passive depletion of intracellular Ca2+ stores using cyclopiazonic acid (10µ)not only caused a rise in [Ca2+]cyt due to Ca2+ influx through store-operated Ca2+ channels, but also mediated a rise in [Ca2+]cyt via the reverse mode of NCX. The upregulated NCX1 in IPAH PASMC led to an enhanced Ca2+ entry via the reverse mode of NCX, but did not accelerate Ca2+ extrusion via the forward mode of NCX. These observations indicate that the upregulated NCX1 and enhanced Ca2+ entry via the reverse mode of NCX are an additional mechanism responsible for the elevated [Ca2+]cyt in PASMC from IPAH patients.
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