Role of Na+/Ca2+ exchange in regulating cytosolic Ca2+ in cultured human pulmonary artery smooth muscle cells

Shen Zhang, Jason X.J. Yuan, Kim E. Barrett, Hui Dong

Research output: Contribution to journalArticle

93 Scopus citations

Abstract

A rise in cytosolic Ca2+ concentration ([Ca2+] cyt) in pulmonary artery smooth muscle cells (PASMC) is an important stimulus for cell contraction, migration, and proliferation. Depletion of intracellular Ca2+ stores opens store-operated Ca2+ channels (SOC) and causes Ca2+ entry. Transient receptor potential (TRP) cation channels that are permeable to Na+ and Ca2+ are believed to form functional SOC. Because sarcolemmal Na+/ Ca 2+ exchanger has also been implicated in regulating [Ca 2+]cyt, this study was designed to test the hypothesis that the Na+/Ca2+ exchanger (NCX) in cultured human PASMC is functionally involved in regulating [Ca2+]cyt by contributing to store depletion-mediated Ca2+ entry. RT-PCR and Western blot analyses revealed mRNA and protein expression for NCX1 and NCKX3 in cultured human PASMC. Removal of extracellular Na+, which switches the Na+/ Ca2+ exchanger from the forward (Ca2+ exit) to reverse (Ca2+ entry) mode, significantly increased [Ca 2+]cyt, whereas inhibition of the Na+/Ca2+ exchanger with KB-R7943 (10 μM) markedly attenuated the increase in [Ca 2+]cyt via the reverse mode of Na+/Ca 2+ exchange. Store depletion also induced a rise in [Ca 2+]cyt via the reverse mode of Na+/Ca 2+ exchange. Removal of extracellular Na+ or inhibition of the Na+/Ca2+ exchanger with KB-R7943 attenuated the store depletion-mediated Ca2+ entry. Furthermore, treatment of human PASMC with KB-R7943 also inhibited cell proliferation in the presence of serum and growth factors. These results suggest that NCX is functionally expressed in cultured human PASMC, that Ca2+ entry via the reverse mode of Na +/Ca2+ exchange contributes to store depletion-mediated increase in [Ca2+]cyt, and that blockade of the Na +/Ca2+ exchanger in its reverse mode may serve as a potential therapeutic approach for treatment of pulmonary hypertension.

Original languageEnglish (US)
Pages (from-to)C245-C252
JournalAmerican Journal of Physiology - Cell Physiology
Volume288
Issue number2 57-2
DOIs
StatePublished - Feb 1 2005
Externally publishedYes

Keywords

  • Calcium homeostasis
  • Sodium-calcium exchange
  • Vascular smooth muscle

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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