Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Institute of Life Sciences, Chongqing Medical University, Chongqing, China.
Lab Invest. 2021 Jul;101(7):897-907. doi: 10.1038/s41374-021-00580-y. Epub 2021 Mar 4.
Sepsis is life-threatening organ dysfunction caused by a deregulated host response to infection. Endothelial dysfunction is the initial factor leading to organ dysfunction and it is associated with increased mortality. There is no effective drug to treat sepsis-induced endothelial dysfunction. In this study, we detected a favorable effect of tubeimoside I (TBM) in ameliorating sepsis-induced endothelial dysfunction. To unveil the mechanism how TBM protects against sepsis-induced endothelial dysfunction, we examined TBM's effects on oxidative stress and apoptosis both in vivo and in vitro. TBM treatment alleviated oxidative stress by decreasing NOX2 and Ac-SOD2/SOD2 and decreased apoptosis by inhibiting cleaved caspse3 and Bax/Bcl-2. Notably, sepsis induced a significant decrease of SIRT3 expression in vascular endothelium, while TBM treatment reversed SIRT3 expression. To clarify whether TBM provides protection via SIRT3, we knockdown SIRT3 using siRNA before TBM treatment. Then, the cytoprotective effects of TBM were largely abolished by siSIRT3. This suggests that SIRT3 plays an essential role in TBM's endothelial protective effects and TBM might be a potential drug candidate to treat sepsis-induced endothelial dysfunction.
脓毒症是一种危及生命的器官功能障碍，由宿主对感染的失调反应引起。内皮功能障碍是导致器官功能障碍的最初因素，与死亡率增加有关。目前尚无有效的药物可治疗脓毒症引起的内皮功能障碍。在这项研究中，我们发现了 tubeimoside I（TBM）在改善脓毒症引起的内皮功能障碍方面的有利作用。为了揭示 TBM 如何保护脓毒症引起的内皮功能障碍的机制，我们在体内和体外检查了 TBM 对氧化应激和细胞凋亡的影响。TBM 通过降低 NOX2 和 Ac-SOD2/SOD2 来减轻氧化应激，通过抑制 cleaved caspase3 和 Bax/Bcl-2 来减少细胞凋亡。值得注意的是，脓毒症导致血管内皮中 SIRT3 的表达显著下降，而 TBM 治疗则逆转了 SIRT3 的表达。为了阐明 TBM 是否通过 SIRT3 提供保护，我们在用 TBM 处理之前使用 siRNA 敲低 SIRT3。然后，siSIRT3 大大消除了 TBM 的细胞保护作用。这表明 SIRT3 在 TBM 的内皮保护作用中起着至关重要的作用，TBM 可能是治疗脓毒症引起的内皮功能障碍的潜在药物候选物。
