Upregulation of Na+/Ca2+ exchanger contributes to the enhanced Ca2+ entry in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension.
A rise in cytosolic Ca(2+) concentration ([Ca(2+)](cyt)) in pulmonary artery smooth muscle cells (PASMC) is a trigger for pulmonary vasoconstriction and a stimulus for PASMC proliferation and migration. Multiple mechanisms are involved in regulating [Ca(2+)](cyt) in human PASMC. The resting [Ca(2+)](cyt) and Ca(2+) 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(+)/Ca(2+) exchanger proteins is upregulated in PASMC from IPAH patients compared with PASMC from normal subjects and patients with other cardiopulmonary diseases. The Na(+)/Ca(2+) exchanger operates in a forward (Ca(2+) exit) and reverse (Ca(2+) entry) mode. By activating the reverse mode of Na(+)/Ca(2+) exchange, removal of extracellular Na(+) caused a rapid increase in [Ca(2+)](cyt), which was significantly enhanced in IPAH PASMC compared with normal PASMC. Furthermore, passive depletion of intracellular Ca(2+) stores using cyclopiazonic acid (10 microM) not only caused a rise in [Ca(2+)](cyt) due to Ca(2+) influx through store-operated Ca(2+) channels but also mediated a rise in [Ca(2+)](cyt) via the reverse mode of Na(+)/Ca(2+) exchange. The upregulated NCX1 in IPAH PASMC led to an enhanced Ca(2+) entry via the reverse mode of Na(+)/Ca(2+) exchange, but did not accelerate Ca(2+) extrusion via the forward mode of Na(+)/Ca(2+) exchange. These observations indicate that the upregulated NCX1 and enhanced Ca(2+) entry via the reverse mode of Na(+)/Ca(2+) exchange are an additional mechanism responsible for the elevated [Ca(2+)](cyt) in PASMC from IPAH patients.
Zhang
Shen
S
Dept. of Medicine, University of California, San Diego, La Jolla, CA 92093-0725, USA.
Dong
Hui
H
Rubin
Lewis J
LJ
Yuan
Jason X-J
JX
D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D007700:Kinetics; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D011651:Pulmonary Artery / Q000166:cytology*; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*; D015854:Up-Regulation
D019831:Sodium-Calcium Exchanger; D012964:Sodium; D002118:Calcium