Simvastatin inhibits apoptosis of endothelial cells induced by sepsis through upregulating the expression of Bcl-2 and downregulating Bax

Fu, Hui; Wang, Qiaosheng; Luo, Qiong; Tan, Song; Su, Hua; Tang, Shilin; Zhao, Zheng-liang; Huang, Liping

doi:10.5847/wjem.j.issn.1920-8642.2014.04.009

Cited by 24 publications

(16 citation statements)

References 39 publications

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“…Previous studies have demonstrated that apoptosis is an important pathological change, which occurs during sepsis (34,35). ECs are important in the host response to sepsis, and endothelial system dysfunction is an important feature of sepsis-associated organ failure and mortality (4).…”

Section: Discussionmentioning

confidence: 99%

Expression of HMGB1 in septic serum induces vascular endothelial hyperpermeability

Zheng

Ding

et al. 2015

Molecular Medicine Reports

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The aim of the present study was to investigate the effects of high mobility group protein B1 (HMGB1), which is expressed in the serum of patients with sepsis, on vascular endothelial permeability. Sera from patients with sepsis were used to treat endothelial cells (ECs), and the effect on endothelial permeability was evaluated using immunofluorescence. The morphologies of endothelial cytoskeletal actin and vascular endothelial (VE)‑cadherin were assessed using laser scanning confocal microscopy. The protein expression levels of HMGB1, B‑cell lymphoma 2 (BCL‑2) and BCL‑2‑associated X protein (BAX) were detected using western blotting. EC apoptosis was measured using flow cytometry. The results demonstrated that HMGB1 was significantly expressed in the serum 24 h following the onset of sepsis, and the expression levels peaked at 48 h, which were sustained until 96 h post‑onset. Compared with the control group, treatment of the ECs with 20% septic serum in vitro significantly increased endothelial monolayer permeability (P<0.01), markedly induced transcellular filamentous (F)‑actin rearrangement with stress fiber formation, and resulted in the localization of VE‑cadherin fragmentations at the cell borders with increased gaps between ECs. Furthermore, flow cytometry showed that the apoptotic rate of ECs was significantly increased following treatment with septic serum. In addition, the expression levels of BAX were significantly increased, whereas the expression levels of BCL‑2 were significantly decreased. Pretreatment with an HMGBI inhibitor (ethyl pyruvate; 5 µM) 24 h prior to treatment with the septic serum attenuated the effects of septic serum treatment. Together, these findings suggested that treatment of ECs with sera from patients with sepsis may induce the loss of vascular endothelial monolayer integrity, elicit the formation of endothelial F‑actin stress fibers and initiate VE‑cadherin redistribution, which may be attributed to high levels of HMGB1 in the serum. This mechanism also appears to involve changes in the activation of BAX and BCL‑2, resulting in EC apoptosis.

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Section: Discussionmentioning

confidence: 99%

Expression of HMGB1 in septic serum induces vascular endothelial hyperpermeability

Zheng

Ding

et al. 2015

Molecular Medicine Reports

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“…Bcl-2 is an important anti-apoptotic protein in vivo, and its main anti-apoptotic mechanisms are as follows: (1) inhibiting the activation of apoptosis protease caspases, including caspase-3; (2) direct antioxidant activity; (3) inhibiting the release of proapoptotic substances; and (4) inhibiting proapoptotic protein Bax 21 . Bax is the most widely distributed proapoptotic protein in the Bcl-2 family 22 . The mechanisms of Bax in promoting apoptosis mainly are as follows:…”

Section: ■ Discussionmentioning

confidence: 99%

Apoptotic mechanisms in rabbits with blast-induced acute lung injury

Hao

Huang

et al. 2018

Acta Cir. Bras.

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To investigate the apoptotic mechanisms in rabbits with blast-induced acute lung injury (ALI). Methods: A total of 40 rabbits were randomly divided into a blank control group (A, n=10) and an experimental group (EXP, n=30). Explosion-induced chest-ALI models were prepared and sampled at different time points (4, 12, and 24h after modeling, T1-T3) to test the lung dry weight/wet weight ratio (W/D) and arterial oxygen pressure (PaO 2), apoptosis of lung tissue by the TUNEL assay, and Caspase-3, Bax, and Bcl-2 levels by immunohistochemical analysis. Furthermore, lung tissue was sampled to observe pathological morphology by microscopy. Results: Under a light microscope, Group EXP exhibited obvious edema in the pulmonary interstitial substance and alveoli, a large number of red blood cells, inflammatory cells, and serous exudation in the alveolar cavity, as well as thickening of the pulmonary interstitial fluid. Compared to Group A, the W/D ratio was significantly increased in Group EXP (P<0.01), while PaO 2 was significantly reduced (P<0.01). The apoptosis index was significantly increased (P<0.01), and caspase-3 and Bax/Bcl-2 levels were increased (P<0.01). Conclusion: Apoptosis plays an important role in the occurrence and development of acute lung injury in rabbits by participating in lung injury and promoting the progression of ALI.

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“…Caspase‐3 is a downstream effector protease and an important contributor to the nuclear changes related to apoptosis (Enari et al, ). The pro‐apoptotic protein, Bax, functions by inducing mitochondria to release cytochrome c, activates caspase‐9, followed by caspase‐3 activation, and thus induces apoptosis (Shi et al, ; Fu et al, ). Our results show that WGP significantly and dose‐dependently inhibited LPS‐induced caspase‐3 activation, which is the terminal event of the extrinsic apoptotic pathway.…”

Section: Discussionmentioning

confidence: 99%

Wheatgrass‐Derived Polysaccharide Has Antiinflammatory, Anti‐Oxidative and Anti‐Apoptotic Effects on LPS‐Induced Hepatic Injury in Mice

Nepali

Lee

et al. 2017

Phytotherapy Research

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Hepatic injury occurs frequently during sepsis, and polysaccharides isolated from plants have been reported to have antiinflammatory and antioxidant effects in various models. However, the effect of wheatgrass-derived polysaccharide (WGP) has not been previously studied. In the present study, we investigated the effect of WGP on lipopolysaccharide (LPS)-induced hepatic injury in mice. Mice were pre-treated with WGP (100 or 200 mg/kg daily for 2 days) and then challenged with LPS (1 mg/kg, intraperitoneal), and sacrificed after 12 h. Wheatgrass-derived polysaccharide decreased serum aminotransferase levels and histological changes as compared with LPS-challenged mice. Wheatgrass-derived polysaccharide also significantly inhibited LPS-induced pro-inflammatory cytokine up-regulation and improved the oxidative status of liver tissues. Furthermore, these effects were found to be mediated by the suppression of the transcriptional activity of nuclear factor-kappa B (NF-κB), due to inhibitions of transforming growth factor beta (TGF-β)-activated kinase (TAK)-1 phosphorylation and inhibition of kappa B (IκB)-α degradation. In addition, WGP inhibited the activations of mitogen-activated protein kinases (MAPKs). Wheatgrass-derived polysaccharide also attenuated hepatic cell death by modulating caspase-3 and apoptosis associated mitochondrial proteins, such as, B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X (Bax). Taken together, WGP possesses antiinflammatory, anti-oxidant and anti-apoptotic activity and ameliorates LPS-induced liver injury in mice. Copyright © 2017 John Wiley & Sons, Ltd.

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Simvastatin inhibits apoptosis of endothelial cells induced by sepsis through upregulating the expression of Bcl-2 and downregulating Bax

Abstract: Our study suggests that simvastatin can inhibit apoptosis of endothelial cells induced by sepsis through upregulating the expression of Bcl-2 and downregulating Bax. It may be one of the mechanisms for simvastatin to treat sepsis.

Cited by 24 publications

References 39 publications

Expression of HMGB1 in septic serum induces vascular endothelial hyperpermeability

Expression of HMGB1 in septic serum induces vascular endothelial hyperpermeability

Apoptotic mechanisms in rabbits with blast-induced acute lung injury

Wheatgrass‐Derived Polysaccharide Has Antiinflammatory, Anti‐Oxidative and Anti‐Apoptotic Effects on LPS‐Induced Hepatic Injury in Mice

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