State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-Based Biomedicine, The Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University, Shanghai 200070, China.
Int J Mol Sci. 2022 Aug 14;23(16):9118. doi: 10.3390/ijms23169118.
Structural and functional alterations of vasculature caused by age-related factors is critically involved in the pathogenesis of ischemic stroke. The longevity genes sirtuins (SIRTs) are extensively investigated in aging-associated pathologies, but their distinct roles in ischemic stroke still remain to be clarified. To address this question, we applied oxygen and glucose deprived/reperfusion (OGD/R) to induce ischemic injury in human endothelial cells (ECs), which are the main component of vasculature in the brain. The results showed that OGD/R led to various damages to ECs, including compromised cell viability, increased LDH release, overproduced ROS, enhanced apoptosis and caspase activity. Meanwhile, the expression of mitochondrial SIRT3 was robustly decreased in ECs after OGD/R treatment. Consistently, rescue of SIRT3 by ectopic expression, but not nuclear SIRT1, in ECs reversed the OGD/R-induced cell damage. Interestingly, some front-line drugs for ischemic stroke, including clopidogrel, aspirin and dl-3-n-butylphthalide (NBP), also rescued SIRT3 and reduced OGD/R-induced endothelial injury, suggesting that the recovery of SIRT3 expression was critical for the protection of these drugs. Moreover, our results demonstrated that 10-hydroxy-NBP (OHNBP), a major metabolite of NBP, showed better blood-brain barrier crossing capability than NBP, but still retained the effects on SIRT3 by NBP. Together, our results suggested that SIRT3 may serve as a potential novel target for treatment of ischemic stroke.
与年龄相关的因素导致的血管结构和功能改变，在缺血性中风的发病机制中起着至关重要的作用。长寿基因沉默信息调节因子（SIRTs）在与衰老相关的病理中被广泛研究，但它们在缺血性中风中的独特作用仍有待阐明。为了解决这个问题，我们应用氧和葡萄糖剥夺/再灌注（OGD/R）来诱导人内皮细胞（ECs）的缺血性损伤，ECs 是大脑血管的主要组成部分。结果表明，OGD/R 导致 ECs 发生各种损伤，包括细胞活力受损、LDH 释放增加、ROS 过度产生、细胞凋亡和半胱天冬酶活性增强。同时，OGD/R 处理后 ECs 中线粒体 SIRT3 的表达明显降低。一致地，ECs 中转染 SIRT3 而不是核 SIRT1 可挽救 SIRT3 的表达，从而逆转 OGD/R 诱导的细胞损伤。有趣的是，一些缺血性中风的一线药物，包括氯吡格雷、阿司匹林和 dl-3-n-丁基邻苯二甲酸（NBP），也可挽救 SIRT3 并减少 OGD/R 诱导的内皮损伤，表明恢复 SIRT3 表达对于这些药物的保护至关重要。此外，我们的结果表明，NBP 的主要代谢物 10-羟基-NBP（OHNBP）比 NBP 具有更好的血脑屏障穿透能力，但仍保留 NBP 对 SIRT3 的作用。总之，我们的结果表明，SIRT3 可能成为治疗缺血性中风的一个潜在的新靶点。
