Procyanidin B2 mitigates endothelial endoplasmic reticulum stress through a PPARδ-Dependent mechanism

Nie, Xin; Tang, Wenjuan; Zhang, Zihui; Yang, Chunmiao; Lei, Qian; Xie, Xinya; Qiang, Erjiao; Zhao, Jingyang; Zhao, Wenfei; Xiao, Lei; Wang, Nanping

doi:10.1016/j.redox.2020.101728

Cited by 33 publications

(18 citation statements)

References 44 publications

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“…In addition, many risk factors, such as oxidized low-density lipoprotein (ox-LDL), blood flow shear force, inflammation cytokines, oxidative stress, and septic shock, contribute to endothelial dysfunction. Among these risk factors, endothelial cells are particularly vulnerable to ox-LDL-induced stress through unknown mechanisms [6][7][8]. Increases in ox-LDL result in decreased proliferative ability, impaired migratory response, increased apoptotic index, and reduced regenerative capability in endothelial cells [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

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Melatonin Attenuates ox‐LDL‐Induced Endothelial Dysfunction by Reducing ER Stress and Inhibiting JNK/Mff Signaling

Xie¹,

Zhong

Guo

et al. 2021

Oxidative Medicine and Cellular Longevity

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Endothelial dysfunction, which is characterized by damage to the endoplasmic reticulum (ER) and mitochondria, is involved in a variety of cardiovascular disorders. Here, we explored whether mitochondrial damage and ER stress are associated with endothelial dysfunction. We also examined whether and how melatonin protects against oxidized low-density lipoprotein- (ox-LDL-) induced damage in endothelial cells. We found that CHOP, GRP78, and PERK expressions, which are indicative of ER stress, increased significantly in response to ox-LDL treatment. ox-LDL also induced mitochondrial dysfunction as evidenced by decreased mitochondrial membrane potential, increased mitochondrial ROS levels, and downregulation of mitochondrial protective factors. In addition, ox-LDL inhibited antioxidative processes, as evidenced by decreased antioxidative enzyme activity and reduced Nrf2/HO-1 expression. Melatonin clearly reduced ER stress and promoted mitochondrial function and antioxidative processes in the presence of ox-LDL. Molecular investigation revealed that ox-LDL activated the JNK/Mff signaling pathway, and melatonin blocked this effect. These results demonstrate that ox-LDL induces ER stress and mitochondrial dysfunction and activates the JNK/Mff signaling pathway, thereby contributing to endothelial dysfunction. Moreover, melatonin inhibited JNK/Mff signaling and sustained ER homeostasis and mitochondrial function, thereby protecting endothelial cells against ox-LDL-induced damage.

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Section: Introductionmentioning

confidence: 99%

“…Endoplasm reticulum (ER) stress is an adaptive response that regulates protein synthesis and folding within cells [6]. Moderate activation of ER stress is associated with timely removal of damaged or unfolded proteins, thereby contributing to protein quality control [12].…”

Section: Introductionmentioning

confidence: 99%

Melatonin Attenuates ox‐LDL‐Induced Endothelial Dysfunction by Reducing ER Stress and Inhibiting JNK/Mff Signaling

Xie¹,

Zhong

Guo

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…The relationship between PPARδ and AMPK is still not clear enough. Activation of PPARδ was shown to increase AMPK phosphorylation and decrease ER stress-induced oxidative stress [29]. In this study, the expression of PPARδ and perilipin were increased by adenine and metformin after HR injury.…”

Section: Discussionmentioning

confidence: 49%

The Cell Protective Effect of Adenine on Hypoxia–Reoxygenation Injury through PPAR Delta Activation

Leu

Wang

Chen

et al. 2021

Life

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Ischemia followed by blood supply reperfusion in cardiomyocytes leads to an overproduction of free radicals and a rapid decrease of adenosine triphosphate concentration. The cardioprotective effect of a potential drug, adenine, was evaluated using H9c2 rat cardiomyoblasts. After hypoxia–reoxygenation (HR) treatment consisting of hypoxia for 21 h followed by reoxygenation for 6 h, it was revealed that pretreatment with 200 µM adenine for 2 h effectively prevented HR-induced cell death. Adenine also significantly decreased the production of reactive oxygen species and reduced cell apoptosis after HR injury. The antioxidant effect of adenine was also revealed in this study. Adenine pretreatment significantly reduced the expression of activating transcription factor 4 (ATF4) and glucose-regulated protein 78 (GRP78) proteins, and protein disulfide isomerase induced a protective effect on mitochondria after HR stimulation. Intracellular adenosine monophosphate-activated protein kinase, peroxisome proliferator-activated receptor delta (PPARδ), and perilipin levels were increased by adenine after HR stimulation. Adenine had a protective effect in HR-damaged H9c2 cells. It may be used in multiple preventive medicines in the future.

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“…ATF6/GRP78 is one of the pathways that regulate endoplasmic reticulum (ER) homeostasis. ER stress can aggravate endothelial cell injury ( Nie et al, 2020 ). In our study, ER stress was activated by H/R, and the levels of ATF6 and GRP78 were increased.…”

Section: Resultsmentioning

confidence: 99%

The Protective Effect of Quercetin on Endothelial Cells Injured by Hypoxia and Reoxygenation

Guo

et al. 2021

Front. Pharmacol.

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Background: Cerebral small vessel disease (CSVD) is a group of clinical syndromes covering all pathological processes of small vessels in the brain, which can cause stroke and serious dementia. However, as the pathogenesis of CSVD is not clear, so the treatment is limited. Endothelial cell dysfunction is earlier than clinical symptoms, such as hypertension and leukosis. Therefore, the treatment of endothelial cells is expected to be a new breakthrough. Quercetin, a flavonoid present in a variety of plants, has the function of anti-inflammation and anti-oxidation. This study aimed to investigate the protective effect of quercetin on endothelial cell injury and provide a basic theory for subsequent application in the clinic.Methods: Human brain microvascular endothelial cells (HBMECs) were cultured in vitro, and the injury model of endothelial cells was established by hypoxia and reoxygenation (H/R). The protective effects of quercetin on HBMECs were studied from the perspectives of cell viability, cell migration, angiogenesis and apoptosis. In order to further study the mechanism of quercetin, oxidative stress and endoplasmic reticulum stress were analyzed. What’s more, blood-brain barrier (BBB) integrity was also studied.Results: Quercetin can promote the viability, migration and angiogenesis of HBMECs, and inhibit the apoptosis. In addition, quercetin can also activate Keap1/Nrf2 signaling pathway, reduce ATF6/GRP78 protein expression. Further study showed that quercetin could increase the expression of Claudin-5 and Zonula occludens-1.Conclusions: Our experiments show that quercetin can protect HBMECs from H/R, which contains promoting cell proliferation, cell migration and angiogenesis, reducing mitochondrial membrane potential damage and inhibiting cell apoptosis. This may be related to its antioxidation and inhibition of endoplasmic reticulum stress. At the same time, quercetin can increase the level of BBB connexin, suggesting that quercetin can maintain BBB integrity.

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Procyanidin B2 mitigates endothelial endoplasmic reticulum stress through a PPARδ-Dependent mechanism

Cited by 33 publications

References 44 publications

Melatonin Attenuates ox‐LDL‐Induced Endothelial Dysfunction by Reducing ER Stress and Inhibiting JNK/Mff Signaling

Melatonin Attenuates ox‐LDL‐Induced Endothelial Dysfunction by Reducing ER Stress and Inhibiting JNK/Mff Signaling

The Cell Protective Effect of Adenine on Hypoxia–Reoxygenation Injury through PPAR Delta Activation

The Protective Effect of Quercetin on Endothelial Cells Injured by Hypoxia and Reoxygenation

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