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首页> 外文期刊>American Journal of Physiology >Tumor necrosis factor-alpha-induced TRPC1 expression amplifies store-operated Ca2+ influx and endothelial permeability.
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Tumor necrosis factor-alpha-induced TRPC1 expression amplifies store-operated Ca2+ influx and endothelial permeability.

机译：肿瘤坏死因子-α诱导的TRPC1表达放大了存储操作的Ca2 +内流和内皮通透性。

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摘要

We determined the effects of TNF-alpha on the expression of transient receptor potential channel (TRPC) homologues in human vascular endothelial cells and the consequences of TRPC expression on the endothelial permeability response. We observed that TNF-alpha exposure increased TRPC1 expression without significantly altering expression of other TRPC isoforms in human pulmonary artery endothelial cells (HPAEC). Because TRPC1 belongs to the store-operated cation channel family, we measured the Ca(2+) store depletion-mediated Ca(2+) influx in response to thrombin exposure. We observed that thrombin-induced Ca(2+) influx in TNF-alpha-stimulated HPAEC was twofold greater than in control cells. To address the relationship between store-operated Ca(2+) influx and TRPC1 expression, we overexpressed TRPC1 by three- to fourfold in the human dermal microvascular endothelial cell line (HMEC) using the TRPC1 cDNA. Thrombin-induced store Ca(2+) depletion in these cells caused approximately twofold greater increase in Ca(2+) influx than in control cells. Furthermore, the inositol 1,4,5-trisphosphate-sensitive store-operated cationic current was increased greater than twofold in TRPC1-transfected cells compared with control. To address the role of Ca(2+) influx via TRPC1 in signaling endothelial permeability, we measured actin-stress fiber formation and transendothelial monolayer electrical resistance (TER) in the TRPC1 cDNA-transfected HMEC and TNF-alpha-challenged HPAEC. Both thrombin-induced actin-stress fiber formation and a decrease in TER were augmented in TRPC1-overexpressing HMEC compared with control cells. TNF-alpha-induced increased TRPC1 expression in HPAEC also resulted in marked endothelial barrier dysfunction in response to thrombin. These findings indicate the expression level of TRPC1 in endothelial cells is a critical determinant of Ca(2+) influx and signaling of the increase in endothelial permeability.
机译：我们确定了TNF-α对人血管内皮细胞中瞬时受体电位通道（TRPC）同源物表达的影响以及TRPC表达对内皮通透性反应的影响。我们观察到，TNF-α暴露可增加TRPC1表达，而不会显着改变人肺动脉内皮细胞（HPAEC）中其他TRPC亚型的表达。由于TRPC1属于存储操作的阳离子通道家族，我们测量了响应凝血酶暴露的Ca（2+）存储耗尽介导的Ca（2+）流入。我们观察到，在TNF-α刺激的HPAEC中，凝血酶诱导的Ca（2+）流入比对照细胞大两倍。为了解决存储操作的Ca（2+）流入与TRPC1表达之间的关系，我们使用TRPC1 cDNA在人类皮肤微血管内皮细胞系（HMEC）中过表达了三到四倍的TRPC1。凝血酶诱导的这些细胞中的Ca（2+）耗竭导致Ca（2+）流入量的增加大约是对照细胞的两倍。此外，与对照相比，在TRPC1转染的细胞中，肌醇1,4,5-三三磷酸敏感性存储操作的阳离子电流增加了两倍以上。为了解决通过TRPC1通过信号传导内皮通透性的Ca（2+）流入的作用，我们在TRPC1 cDNA转染的HMEC和TNF-α挑战的HPAEC中测量了肌动蛋白应力纤维形成和跨内皮单层电阻（TER）。与对照细胞相比，在过表达TRPC1的HMEC中，凝血酶诱导的肌动蛋白应激纤维的形成和TER的减少都增加了。 TNF-α诱导的HPAEC中TRPC1表达的增加也导致了对凝血酶的明显内皮屏障功能障碍。这些发现表明内皮细胞中TRPC1的表达水平是Ca（2+）流入和内皮通透性增加的信号的关键决定因素。

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