Redox Biology
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2023
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IF 11.4
Tao Jiang,Tao Qin,Peng Gao,Zhiwen Tao,Xiaowei Wang,Mengyuan Wu,Jun Gu,Bo Chu,Ziyang Zheng,Jiang Yi,Tao Xu,Yifan Huang,Hao Liu,Shujie Zhao,Yongxin Ren,Jian Chen,Guoyong Yin
Disruption of the blood-spinal cord barrier (BSCB) leads to inflammatory cell infiltration and neural cell death, thus, contributing to poor functional recovery after spinal cord injury (SCI). Previous studies have suggested that Sirtuin 1 (SIRT1), an NAD + -dependent class III histone deacetylase, is abundantly expressed in endothelial cells and promotes endothelial homeostasis. However, the role of SIRT1 in BSCB function after SCI remains poorly defined. Here, we report that SIRT1 is highly expressed in spinal cord endothelial cells, and its expression significantly decreases after SCI. Using endothelial cell-specific SIRT1 knockout mice, we observed that endothelial cell-specific knockout of SIRT1 aggravated BSCB disruption, thus, resulting in widespread inflammation, neural cell death and poor functional recovery after SCI. In contrast, activation of SIRT1 by the agonist SRT1720 had beneficial effects. In vitro, knockdown of SIRT1 exacerbated IL-1β-induced endothelial barrier disruption in bEnd.3 cells, whereas overexpression of SIRT1 was protective. Using RNA-seq and IP/MS analysis, we identified p66Shc, a redox protein, as the potential target of SIRT1. Further studies demonstrated that SIRT1 interacts with and deacetylates p66Shc, thereby attenuating oxidative stress and protecting endothelial barrier function. Overall, our results indicate that SIRT1 decreases endothelial ROS production and attenuates BSCB disruption by deacetylating p66Shc after SCI, and suggest that SIRT1 activation has potential as a therapeutic approach to promote functional recovery against BSCB disruption following SCI.
研究领域:
神经科学
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分子生物学
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病理生理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NUTRITIONAL BIOCHEMISTRY
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2025
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IF 4.9
Heng Zhou,Yueming Long,Fangmei Yu,Chenhui Ji,Li Gui,Yunxia Lu
Resveratrol (RSV) ameliorates endothelial dysfunction (ED) primarily through sirtuin 1 (SIRT1). Increasing evidence shows pyroptosis as a novel mechanism in palmitic acid (PA)-induced ED. p66Shc is an adaptor protein involved in oxidative stress. However, whether RSV attenuates the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome via p66Shc remains elusive. This study aims to evaluate whether the anti-pyroptotic effect of RSV and the SIRT1 inhibitor EX527 are related to p66Shc. High-fat diet (HFD) induced obesity in mice, and RSV was administered intragastrically with 400mg/kg/d for 22 successive weeks. The serum levels of interleukin-1β (IL-1β) and IL-18 were analyzed, and the expression of related proteins were assayed with immunohistochemistry in the thoracic aorta. human umbilical vein endothelial cells (HUVECs) were induced by PA, then treated with RSV and EX527 respectively, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP) and expression of p66Shc, NLRP3, GSDMD and pyroptosis-related genes were assayed. RSV administration ameliorated endothelial cell pyroptosis by decreasing serum IL-1β and IL-18, the expression of NLRP3, p66Shc, and gasdermin D (GSDMD), and increasing the expression of SIRT1 in the HFD-treated thoracic aorta. PA promoted GSDMD-mediated endothelial cell pyroptosis by ROS production, LDH release, decreased MMP and SIRT1 expression, increased expression of p66Shc and activation of the NLRP3 inflammasome in a dose-dependent manner. RSV attenuated PA-induced pyroptosis, whereas EX527 reversed the antipyroptotic effect of RSV in PA-treated HUVECs. Our results suggested a new mechanism that RSV improves PA-induced pyroptosis in endothelial cells via the SIRT1-p66Shc-NLRP3 pathway.
研究领域:
药理学
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分子生物学
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心血管科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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