Upregulation of Na+/Ca2+ exchanger contributes to the enhanced Ca2+ entry in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension

Shen Zhang, Hui Dong, Lewis J. Rubin, Jason X.J. Yuan

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

A rise in cytosolic Ca2+ concentration ([Ca2+] 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 [Ca2+] cyt in human PASMC. 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 Na +/Ca2+ exchanger operates in a forward (Ca2+ exit) and reverse (Ca2+ entry) mode. By activating the reverse mode of Na+/Ca2+ exchange, 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 (10 μM) not only caused a rise in [Ca2+] cyt due to Ca2+ influx through store-operated Ca 2+ channels but also mediated a rise in [Ca2+] cyt via the reverse mode of Na+/Ca2+ exchange. The upregulated NCX1 in IPAH PASMC led to an enhanced Ca2+ entry via the reverse mode of Na+/Ca2+ exchange, but did not accelerate Ca2+ extrusion via the forward mode of Na +/Ca2+ exchange. These observations indicate that the upregulated NCX1 and enhanced Ca2+ entry via the reverse mode of Na+/Ca2+ exchange are an additional mechanism responsible for the elevated [Ca2+]cyt in PASMC from IPAH patients.

Original languageEnglish (US)
Pages (from-to)C2297-C2305
JournalAmerican Journal of Physiology - Cell Physiology
Volume292
Issue number6
DOIs
StatePublished - Jun 2007

Keywords

  • Proliferation
  • Reverse and forward mode
  • Transient receptor potential channel

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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