Bone morphogenetic protein 4 enhances canonical transient receptor potential expression, store-operated Ca2+ entry, and basal [Ca2+]i in rat distal pulmonary arterial smooth muscle cells
Bone morphogenetic protein 4 enhances canonical transient receptor potential expression, store-operated Ca2+ entry, and basal [Ca2+]i in rat distal pulmonary arterial smooth muscle cells
复制标题
骨形态发生蛋白 4 增强大鼠远端肺动脉平滑肌细胞中的典型瞬时受体电位表达、钙池操纵的 Ca2 进入和基础 [Ca2]i
DOI：
10.1152/ajpcell.00040.2010
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发表时间：
2010-12-01
影响因子：
5.5
通讯作者：
Wang, Jian
中科院分区：
文献类型：
--
作者：
Lu, Wenju;Ran, Pixin;Wang, Jian
Lu W，Ran P，Zhang D，Lai N，Zhong N，Wang J. Bone morphogenetic protein 4 enhances canonical transient receptor potential expression，store-operated Ca2+ entry，and basal [Ca2+]（i）in rat distal pulmonary arterial smooth muscle cells.美国生理学杂志细胞生理学299：C1370-C1378，2010年。首次发表于2010年9月15日; doi：10.1152/ajpcell.00040.2010。骨形态发生蛋白4（BMP 4）在肺血管重建中的重要作用已被证实，但其机制尚不清楚。我们以前发现，钙池操纵的钙通道（SOCC），主要被认为是典型的瞬时受体电位（TRPC）蛋白组成的钙内流，可能有助于慢性缺氧性肺动脉高压的发病发展。本研究探讨了BMP 4对肺动脉平滑肌细胞TRPC表达和钙池操纵性内流（SOCE）的影响。实时定量PCR和Western blotting显示，BMP 4（50 ng/ml，60 h）处理增加TRPC 1，TRPC 4和TRPC 6 mRNA和蛋白表达在生长停滞的大鼠远端PASMCs。此外，与媒介物对照相比，用BMP 4处理的细胞也表现出增强的SOCE，和升高的基础细胞内钙浓度（[Ca 2 +]i），如通过荧光显微镜使用Ca 2+指示剂Fura-2 AM所测定的。用无Ca 2+的Krebs-Ringer碳酸氢盐溶液（KRBS）或含有SOCC拮抗剂SKF-96365或NiCl 2的KRBS灌注细胞减弱了由BMP 4引起的基础[Ca 2 +]（i）的增加。小干扰RNA特异性敲除BMP 4可显着降低TRPC 1、TRPC 4和TRPC 6的mRNA和蛋白表达，并降低血清刺激的PASMC中的SOCE和基础[Ca 2 +]（i）。我们的结论是，BMP 4可能通过上调TRPC表达来调节PASMCs中的钙信号，导致PASMCs中SOCE和基础[Ca 2 +]（i）增加，并通过这种机制促进肺动脉高压期间的肺血管重构。
Lu W, Ran P, Zhang D, Lai N, Zhong N, Wang J. Bone morphogenetic protein 4 enhances canonical transient receptor potential expression, store-operated Ca2+ entry, and basal [Ca2+](i) in rat distal pulmonary arterial smooth muscle cells. Am J Physiol Cell Physiol 299: C1370-C1378, 2010. First published September 15, 2010; doi:10.1152/ajpcell.00040.2010.-Recent advances have identified an important role of bone morphogenetic protein 4 (BMP4) in pulmonary vascular remodeling, yet the underlying mechanisms remain largely unexplored. We have previously found that Ca2+ influx through store-operated calcium channels (SOCC), which are mainly thought to be composed of canonical transient receptor potential (TRPC) proteins, likely contribute to the pathogenic development of chronic hypoxic pulmonary hypertension. In this study, we investigated the effect of BMP4 on expression of TRPC and store-operated Ca2+ entry (SOCE) in pulmonary arterial smooth muscle cells (PASMCs). Real-time quantitative PCR and Western blotting revealed that treatment with BMP4 (50 ng/ml, 60 h) increased TRPC1, TRPC4, and TRPC6 mRNA and protein expression in growth-arrested rat distal PASMCs. Moreover, in comparison to vehicle control, cells treated with BMP4 also exhibited enhanced SOCE, and elevated basal intracellular calcium concentration ([Ca2+]i) as determined by fluorescent microscopy using the Ca2+ indicator Fura-2 AM. Perfusing cells with Ca2+-free Krebs-Ringer bicarbonate solution (KRBS) or KRBS containing SOCC antagonists SKF-96365 or NiCl2 attenuated the increases in basal [Ca2+](i) caused by BMP4. Specific knockdown of BMP4 by small interference RNA significantly decreased the mRNA and protein expression of TRPC1, TRPC4, and TRPC6 and reduced SOCE and basal [Ca2+](i) in serum-stimulated PASMCs. We conclude that BMP4 regulates calcium signaling in PASMCs likely via upregulation of TRPC expression, leading to enhanced SOCE and basal [Ca2+](i) in PASMCs, and by this mechanism contributes to pulmonary vascular remodeling during pulmonary arterial hypertension.