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1 Department of Medicine, University of California, San Diego, La Jolla, CA, USA
* To whom correspondence should be addressed. E-mail: h2dong{at}ucsd.edu.
A rise in cytosolic Ca2+ ([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. Since sarcolemmal Na+-Ca2+ exchanger has also been implicated in regulating [Ca2+]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 [Ca2+]cyt, while inhibition of the Na+-Ca2+ exchanger with KB-R7943 (10 µM) markedly attenuated the increase in [Ca2+]cyt via the reverse mode of Na+-Ca2+ exchange. Store depletion also induced a rise in [Ca2+]cyt via the reverse mode of Na+-Ca2+ 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 the Na+-Ca2+ exchanger is functionally expressed in cultured human PASMC. The Ca2+ entry via the reverse mode of Na+-Ca2+ exchange contributes to store depletion-mediated increase in [Ca2+]cyt. Blockade of the Na+-Ca2+ exchanger in its reverse mode may serve as a potential therapeutic approach for treatment of pulmonary hypertension.
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