Bosentan inhibits transient receptor potential channel expression in pulmonary vascular myocytes
Bosentan inhibits transient receptor potential channel expression in pulmonary vascular myocytes
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DOI：
10.1164/rccm.200312-1668oc
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发表时间：
2004-11-15
影响因子：
24.7
通讯作者：
Yuan, JXJ
中科院分区：
文献类型：
--
作者：
Kunichika, N;Landsberg, JW;Yuan, JXJ
波生坦是一种双重内皮素受体阻滞剂，临床上已用于治疗特发性肺动脉高压（IPAH）。然而，其抗肺动脉平滑肌细胞（PASMC）增殖作用的机制仍不清楚。细胞质 Ca2+ 的增加刺激 PASMC 增殖，而经典瞬时受体电位 (TRPC) 通道是 PASMC 增殖过程中 Ca2+ 进入的重要途径。波生坦 (20-50 muM) 显着抑制内皮素-1 或血小板衍生生长因子 (PDGF) 介导的 PASMC 生长和 [H-3] 胸苷摄取。在 PASMC 中，内皮素-1 (1 muM) 和 PDGF (10 ng/ml) 均上调 TRPC6 蛋白表达，而波生坦显着下调 TRPC6 蛋白水平。此外，IPAH患者PASMCs中TRPC6的表达高于正常PASMCs，且与正常PASMCs相比，波生坦在IPAH-PASMCs中的抗增殖作用显着增强。这些观察结果表明，波生坦对 PASMC 的抗增殖作用涉及通过可能独立于内皮素受体阻断的机制下调 TRPC6 通道。波生坦对 IPAH-PASMC 的影响大于对正常 PASMC 的影响，表明 TRPC6 表达和功能的增加可能与 IPAH 患者 PASMC 的过度生长有关。
Bosentan, a dual endothelin receptor blocker, has been used clinically to treat idiopathic pulmonary arterial hypertension (IPAH). However, the mechanism of its antiproliferative effect on pulmonary artery smooth muscle cells (PASMCs) remains unclear. A rise in cytoplasmic Ca2+ stimulates PASMC proliferation and the canonical transient receptor potential (TRPC) channels are an important pathway for Ca2+ entry during PASMC proliferation. Bosentan (20-50 muM) significantly inhibited endothelin-1- or platelet-derived growth factor (PDGF)-mediated PASMC growth and [H-3]thymidine uptake. In PASMCs, endothelin-1 (1 muM) and PDGF (10 ng/ml) both upregulated protein expression of TRPC6, whereas bosentan markedly downregulated TRPC6 protein levels. Furthermore, TRPC6 expression in PASMCs from patients with IPAH was greater than in normal PASMCs, and the anti proliferative effect of bosentan was significantly enhanced in IPAH-PASMCs in comparison with normal PASMCs. These observations demonstrate that the antiproliferative effect of bosentan on PASMCs involves the downregulation of TRPC6 channels via a mechanism possibly independent of endothelin receptor blockade. The greater effect of bosentan on IPAH-PASMCs than on normal PASMCs suggests that increased TRPC6 expression and function may be involved in the overgrowth of PASMCs in patients with IPAH.