Enhanced Ca(2+)-sensing receptor function in idiopathic pulmonary arterial hypertension.
Enhanced Ca(2+)-sensing receptor function in idiopathic pulmonary arterial hypertension.
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DOI：
10.1161/circresaha.112.266361
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发表时间：
2012-08-03
影响因子：
20.1
通讯作者：
Yuan JX
中科院分区：
文献类型：
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作者：
Yamamura A;Guo Q;Yamamura H;Zimnicka AM;Pohl NM;Smith KA;Fernandez RA;Zeifman A;Makino A;Dong H;Yuan JX
肺动脉平滑肌细胞（PASMC）胞浆Ca ~（2+）浓度（[Ca ~（2+）]cyt）升高是肺血管收缩和血管重构的重要刺激因素。特发性肺动脉高压（IPAH）患者PASMC中静息[Ca 2 +]cyt增加和Ca 2+内流增加。我们研究了细胞外Ca 2+敏感受体（CaSR）是否参与了IPAH-PASMC中Ca 2+内流和增殖的增强，以及阻断CaSR是否抑制实验性肺动脉高压。在正常PASMC灌流无Ca ~（2+）溶液中，加入2.2mM Ca ~（2+）对细胞内[Ca ~（2+）]cyt的影响很小。然而，在IPAH-PASMC中，细胞外Ca 2+的恢复引起[Ca 2 +]cyt的显著增加。细胞外应用精胺可使IPAH-PASMC胞浆内[Ca ~（2+）]_（cytt）明显升高，但对正常PASMC无明显影响。拟钙R568增强IPAH-PASMC细胞外Ca ~（2+）诱导的细胞内[Ca ~（2+）]_（cyt）升高，而钙离子拮抗剂R5143减弱。IPAH-PASMC中CaSR的蛋白表达水平高于正常PASMC，siRNA敲低IPAH-PASMC中CaSR可抑制细胞外Ca ~（2+）介导的细胞内[Ca ~（2+）]_（cyt）升高，抑制IPAH-PASMC增殖。使用肺动脉高压的动物模型，我们的数据表明，在PASMC中的CaSR表达和功能均增强，而腹膜内注射calcilytic RP 2143可防止注射野百合碱的大鼠和暴露于缺氧的小鼠的肺动脉高压和右心室肥大的发展。细胞外Ca 2+诱导的[Ca 2 +]cyt增加是由于上调CaSR导致的，这是导致肺动脉高压患者和动物中Ca 2+内流增加和PASMC过度增殖的一种新的致病机制。
A rise in cytosolic Ca2+ concentration ([Ca2+]cyt) in pulmonary arterial smooth muscle cells (PASMC) is an important stimulus for pulmonary vasoconstriction and vascular remodeling. Increased resting [Ca2+]cyt and enhanced Ca2+ influx have been implicated in PASMC from patients with idiopathic pulmonary arterial hypertension (IPAH). We examined whether the extracellular Ca2+-sensing receptor (CaSR) is involved in the enhanced Ca2+ influx and proliferation in IPAH-PASMC and whether blockade of CaSR inhibits experimental pulmonary hypertension. In normal PASMC superfused with Ca2+-free solution, addition of 2.2 mM Ca2+ to the perfusate had little effect on [Ca2+]cyt. In IPAH-PASMC, however, restoration of extracellular Ca2+ induced a significant increase in [Ca2+]cyt. Extracellular application of spermine also markedly raised [Ca2+]cyt in IPAH-PASMC, but not in normal PASMC. The calcimimetic R568 enhanced, whereas the calcilytic NPS 2143 attenuated, the extracellular Ca2+-induced [Ca2+]cyt rise in IPAH-PASMC. Furthermore, the protein expression level of CaSR in IPAH-PASMC was greater than in normal PASMC; knockdown of CaSR in IPAH-PASMC with siRNA attenuated the extracellular Ca2+-mediated [Ca2+]cyt increase and inhibited IPAH-PASMC proliferation. Using animal models of pulmonary hypertension, our data showed that CaSR expression and function were both enhanced in PASMC, whereas intraperitoneal injection of the calcilytic NPS 2143 prevented the development of pulmonary hypertension and right ventricular hypertrophy in rats injected with monocrotaline and mice exposed to hypoxia. The extracellular Ca2+-induced increase in [Ca2+]cyt due to upregulated CaSR is a novel pathogenic mechanism contributing to the augmented Ca2+ influx and excessive PASMC proliferation in patients and animals with pulmonary arterial hypertension.