Upregulation of Na+/Ca2+ exchanger contributes to the enhanced Ca2+ entry in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension
Upregulation of Na+/Ca2+ exchanger contributes to the enhanced Ca2+ entry in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension
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DOI：
10.1152/ajpcell.00383.2006
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发表时间：
2007-06-01
影响因子：
5.5
通讯作者：
Yuan, Jason X. -J.
中科院分区：
文献类型：
--
作者：
Zhang, Shen;Dong, Hui;Yuan, Jason X. -J.
肺动脉平滑肌细胞（PASMC）胞浆Ca ~（2+）浓度（[Ca ~（2+）]（cyt））升高是肺血管收缩的触发因素，也是PASMC增殖和迁移的刺激因素。多种机制参与调节人PASMC [Ca 2 +]（cyt）。特发性肺动脉高压（IPAH）患者PASMC胞浆内Ca 2+和胞浆内Ca 2+含量均增加，这被认为是IPAH患者持续性肺血管收缩和过度肺血管重构的重要机制。在这里，我们报告的蛋白表达的NCX 1，NCX家族成员的Na 2 +/Ca 2+交换蛋白的上调PASMC从IPAH患者相比，从正常人和其他心肺疾病患者。Na+/Ca 2+交换器以正向（Ca 2+退出）和反向（Ca 2+进入）模式运行。通过激活Na+/Ca 2+交换的反向模式，去除细胞外Na+引起[Ca 2 +] cyt的快速增加，与正常PASMC相比，IPAH PASMC中[Ca 2 +] cyt显著增强。此外，使用cyclopiazonic酸（10 μ M）的细胞内Ca 2+商店的被动耗竭不仅引起了[Ca 2 +]细胞色素的上升，由于通过商店操作的Ca 2+通道的Ca 2+内流，但也介导了[Ca 2 +]细胞色素的上升通过Na+/Ca 2+交换的反向模式。IPAH PASMC中上调的NCX 1通过Na+/Ca 2+交换的反向模式导致Ca 2+进入增加，但不通过Na+/Ca 2+交换的正向模式促进Ca 2+排出。这些观察结果表明，通过Na+/Ca 2+交换的反向模式上调的NCX 1和增强的Ca 2+进入是IPAH患者PASMC中[Ca 2 +] cyt升高的另一机制。
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 Na2+/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 mu M) 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 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.