Role of thiosulfate in hydrogen sulfide-dependent redox signaling in endothelial cells
Role of thiosulfate in hydrogen sulfide-dependent redox signaling in endothelial cells
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DOI：
10.1152/ajpheart.00723.2016
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发表时间：
2017-08-01
影响因子：
4.8
通讯作者：
Shen, Xinggui
中科院分区：
文献类型：
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作者：
Leskova, Anna;Pardue, Sibile;Shen, Xinggui
最近的报道显示，硫化氢(H_2S)在促进心血管稳态和健康方面发挥着关键作用。硫代硫酸盐是H_2S氧化代谢的产物之一，已被广泛且安全地用于治疗透析患者的钙化性尿毒症动脉病变。然而，尽管硫代硫酸盐和H_2S在氧化还原信号传递过程中如何相互作用，其基本问题仍未得到解答。在本研究中，我们研究了外源性硫代硫酸盐对缺氧诱导的人脐静脉内皮细胞(HUVECs)中H_2S代谢产物生物利用度的影响。在低氧条件下，HUVECs内GSH和GSSG水平在0.5h和4h显著降低，游离H_2S和酸不稳定硫化物在各时间点均降低，结合硫化物增加。外源性硫代硫酸盐显著降低缺氧0.5h时HUVECs中GSH/GSSG/总硫化物的比值，而在缺氧4h时显著增加这一比值。这些反应表明，硫代硫酸盐在低剂量和高剂量以及在不同的氧分压下具有不同的作用。此外，在常氧和低氧条件下，硫代硫酸盐处理也降低了血管内皮生长因子诱导的半胱氨酸-伽玛裂解酶的表达，并降低了血管内皮生长因子诱导的血管内皮细胞增殖。这些结果表明，硫代硫酸盐可以在不同的培养条件下调节影响血管生成活性的硫化氢代谢产物和信号转导。因此，硫代硫酸盐可能是一种独特的硫化物供体，在涉及血管生成的病理生理条件下调节内皮细胞的反应。新和值得注意的是，本报告提供了新的证据，表明不同水平的外源性硫代硫酸盐在常氧或低氧条件下动态改变内皮细胞离散的硫化物生化代谢产物的生物利用度，以缓慢的方式调节硫化物代谢产物。此外，我们的研究结果还显示，硫代硫酸盐出人意料地抑制了依赖血管内皮生长因子的内皮细胞的增殖，这与降低胱硫醚-伽马裂解酶蛋白水平有关。
Recent reports have revealed that hydrogen sulfide (H2S) exerts critical actions to promote cardiovascular homeostasis and health. Thiosulfate is one of the products formed during oxidative H2S metabolism, and thiosulfate has been used extensively and safely to treat calcific uremic arteriopathy in dialysis patients. Yet despite its significance, fundamental questions regarding how thiosulfate and H2S interact during redox signaling remain unanswered. In the present study, we examined the effect of exogenous thiosulfate on hypoxia-induced H2S metabolite bioavailability in human umbilical vein endothelial cells (HUVECs). Under hypoxic conditions, we observed a decrease of GSH and GSSG levels in HUVECs at 0.5 and 4 h as well as decreased free H2S and acid-labile sulfide and increased bound sulfide at all time points. Treatment with exogenous thiosulfate significantly decreased the ratio of GSH/GSSG to total sulfide of HUVECs under 0.5 h of hypoxia but significantly increased this ratio in HUVECs under 4 h of hypoxia. These responses reveal that thiosulfate has different effects at low and high doses and under different O-2 tensions. In addition, treatment with thiosulfate also diminished VEGF-induced cystathionine-gamma-lyase expression and reduced VEGF-induced HUVEC proliferation under both normoxic and hypoxic conditions. These results indicate that thiosulfate can modulate H2S metabolites and signaling under various culture conditions that impact angiogenic activity. Thus, thiosulfate may serve as a unique sulfide donor to modulate endothelial responses under pathophysiological conditions involving angiogenesis.NEW & NOTEWORTHY This report provides new evidence that different levels of exogenous thiosulfate dynamically change discrete sulfide biochemical metabolite bioavailability in endothelial cells under normoxia or hypoxia, acting in a slow manner to modulate sulfide metabolites. Moreover, our findings also reveal that thiosulfate surprisingly inhibits VEGF-dependent endothelial cell proliferation associated with a reduction in cystathionine-gamma-lyase protein levels.