Rescue of Mitochondrial SIRT3 Ameliorates Ischemia-like Injury in Human Endothelial Cells

Abstract

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.

Alzheimer’s Amyloid-β Accelerates Cell Senescence and Suppresses SIRT1 in Human Neural Stem Cells

“…Lentivirus was prepared as previously reported [29]. In brief, we transfected HEK293T cells with psPAX2 (15 µg), pMD2.G (10 µg), and FUGW-SIRT1 (20 µg) plasmids using polyethyleneimine (PEI).…”

Sirtuin-3: A potential target for treating several types of brain injury

“…Recent studies have found that modulating the tunneling nanotubes formation and transcellular mitochondria transfer is a promising strategy for the treatment of ischemic stroke ( Luchetti et al, 2022 ), however, the relationship between Sirt3 and tunneling nanotubes formation and transcellular mitochondria transfer remains unclear. Changes in the blood-brain barrier directly caused by endothelial injury play a significant role in the pathogenesis of ischaemic stroke ( Yang X. et al, 2021 ), and SIRT3 plays a critical role in alleviating vascular endothelial injury after stroke ( Liu et al, 2022 ). In addition, SIRT3 can aid neurovascular recovery in an ischaemic stroke model ( Yang X. et al, 2018 ).…”

Sirtuins: Promising Therapeutic Targets to Treat Ischemic Stroke

“…This mechanism could be associated with the deacetylating of FOXO3a, increasing the activity of the antioxidant enzyme SOD2 and reducing ROS production [ 17 ]. Similarly, recent evidence indicates that SIRT3 overexpression effectively attenuates ROS overproduction induced by oxygen–glucose deprivation/reperfusion (OGD/R) in HUVECs [ 107 ].…”