Leskova Anna, Pardue Sibile, Glawe John D, Kevil Christopher G, Shen Xinggui
Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana.
Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana
Am J Physiol Heart Circ Physiol. 2017 Aug 1;313(2):H256-H264. doi: 10.1152/ajpheart.00723.2016. Epub 2017 May 26.
Recent reports have revealed that hydrogen sulfide (HS) exerts critical actions to promote cardiovascular homeostasis and health. Thiosulfate is one of the products formed during oxidative HS 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 HS interact during redox signaling remain unanswered. In the present study, we examined the effect of exogenous thiosulfate on hypoxia-induced HS 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 HS 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 tensions. In addition, treatment with thiosulfate also diminished VEGF-induced cystathionine-γ-lyase expression and reduced VEGF-induced HUVEC proliferation under both normoxic and hypoxic conditions. These results indicate that thiosulfate can modulate HS 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. 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-γ-lyase protein levels.
最近的报告显示，硫化氢（HS）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HS氧化代谢过程中形成的产物之一，并且硫代硫酸盐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。然而，尽管其具有重要意义，但关于硫代硫酸盐和HS在氧化还原信号传导过程中如何相互作用的基本问题仍未得到解答。在本研究中，我们检测了外源性硫代硫酸盐对人脐静脉内皮细胞（HUVECs）中缺氧诱导的HS代谢物生物利用度的影响。在缺氧条件下，我们观察到HUVECs在0.5小时和4小时时谷胱甘肽（GSH）和氧化型谷胱甘肽（GSSG）水平降低，并且在所有时间点游离HS和酸不稳定硫化物减少而结合硫化物增加。在缺氧0.5小时时，用外源性硫代硫酸盐处理显著降低了HUVECs中GSH/GSSG与总硫化物的比率，但在缺氧4小时时显著增加了该比率。这些反应表明硫代硫酸盐在低剂量和高剂量以及不同氧张力下具有不同的作用。此外，在常氧和缺氧条件下，用硫代硫酸盐处理也减少了血管内皮生长因子（VEGF）诱导的胱硫醚-γ-裂解酶表达并降低了VEGF诱导的HUVECs增殖。这些结果表明，硫代硫酸盐可以在影响血管生成活性的各种培养条件下调节HS代谢物和信号传导。因此，在涉及血管生成的病理生理条件下，硫代硫酸盐可能作为一种独特的硫化物供体来调节内皮反应。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缺氧条件下动态改变内皮细胞中离散的硫化物生化代谢物生物利用度，以缓慢的方式调节硫化物代谢物。此外，我们的研究结果还表明，硫代硫酸盐出人意料地抑制了与胱硫醚-γ-裂解酶蛋白水平降低相关的VEGF依赖性内皮细胞增殖。
