Knockdown of sestrin2 increases pro-inflammatory reactions and ER stress in the endothelium via an AMPK dependent mechanism

Hwang, Hwan Jin; Jung, Tae Woo; Choi, Jun Ho; Lee, Hyun Jung; Chung, Haegeun; Seo, Ji A; Kim, Sin Gon; Kim, Nan Hee; Choi, Kyung Mook; Choi, Dong Seop; Baik, Sei Hyun; Yoo, Hye Jin

doi:10.1016/j.bbadis.2017.02.018

Cited by 57 publications

(41 citation statements)

References 30 publications

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“…After 1 day, heart tissue was harvested. A detailed experimental design is described in our previous report [ 17 ]. This study was approved by the Institutional Animal Care and Use Committee (IACUC) of Korea University (Seoul, Korea).…”

Section: Methodsmentioning

confidence: 99%

“…Park et al [ 15 ] reported that obesity-induced hepatic endoplasmic reticulum (ER) stress and apoptosis were elevated in sesn2-deficient mice compared to normal mice. In vascular endothelial cells, inhibition of sesn2 was shown to elevate ROS production and cytotoxicity induced by inflammatory stimuli [ 16 , 17 ]. Although growing evidence suggests that sesn2 protects against various cardiometabolic diseases such as nonalcoholic fatty liver disease (NAFLD) and atherosclerosis, it is unclear whether sesn2 has a beneficial effect against cardiomyopathy-related molecular events.…”

Section: Introductionmentioning

confidence: 99%

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Knockdown of Sestrin2 Increases Lipopolysaccharide-Induced Oxidative Stress, Apoptosis, and Fibrotic Reactions in H9c2 Cells and Heart Tissues of Mice via an AMPK-Dependent Mechanism

Hwang

Kim

Chung

et al. 2018

Mediators of Inflammation

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Sestrin2 (sesn2) is an endogenous antioxidant protein that has recently gained attention for its potential to treat various inflammatory diseases. However, the relationship of sesn2 with cardiomyopathy is still unclear. In H9c2 cells, sesn2 knockdown reduced the level of 5′ adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, downregulated antioxidant genes including catalase and superoxide dismutase (SOD2), and increased reactive oxygen species (ROS) production upon lipopolysaccharide (LPS) treatment. LPS-mediated cell death and the expression of matrix metalloproteinase (MMP) 2 and MMP9 were significantly increased by sesn2 knockdown. However, these increases were prevented by treatment with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK activator. Consistent with the in vitro results, AMPK phosphorylation was decreased in heart tissue from sesn2 knockdown mice compared to heart tissue from control C57BL/6 mice, which was associated with decreased expression of antioxidant genes and increased LPS-mediated cell death signaling. Furthermore, the decrease in AMPK phosphorylation caused by sesn2 knockdown increased LPS-mediated expression of cardiac fibrotic factors, including collagen type I and type III, in addition to MMP2 and MMP9, in heart tissue from C57BL/6 mice. These results suggest that sesn2 is a novel potential therapeutic target for cardiomyopathy under inflammatory conditions.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Knockdown of Sestrin2 Increases Lipopolysaccharide-Induced Oxidative Stress, Apoptosis, and Fibrotic Reactions in H9c2 Cells and Heart Tissues of Mice via an AMPK-Dependent Mechanism

Hwang

Kim

Chung

et al. 2018

Mediators of Inflammation

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“…Indeed, it was recently shown that knockdown of Sestrin2 potentiates the formation of atherosclerotic plaques and other hallmarks of atherosclerosis in mice [50]. The underlying mechanism for this effect appears to involve increased ROS production and ER stress as well as increased adhesion molecules in the vasculature [50]. Taken together, Sestrins 1 and 2 may prove to be attractive targets for amelioration of cardiovascular diseases.…”

Section: Significance Of Sestrins In Diseasesmentioning

confidence: 99%

Sestrin2 as a Novel Biomarker and Therapeutic Target for Various Diseases

Pasha

Eid

et al. 2017

Oxidative Medicine and Cellular Longevity

128

130

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Sestrin2 (SESN2), a highly conserved stress-inducible metabolic protein, is known to repress reactive oxygen species (ROS) and provide cytoprotection against various noxious stimuli including genotoxic and oxidative stress, endoplasmic reticulum (ER) stress, and hypoxia. Studies demonstrate that the upregulation of Sestrin2 under conditions of oxidative stress augments autophagy-directed degradation of Kelch-like ECH-associated protein 1 (Keap1), which targets and breaks down nuclear erythroid-related factor 2 (Nrf2), a key regulator of various antioxidant genes. Moreover, ER stress and hypoxia are shown to induce Sestrins, which ultimately reduce cellular ROS levels. Sestrin2 also plays a pivotal role in metabolic regulation through activation of the key energy sensor AMP-dependent protein kinase (AMPK) and inhibition of mammalian target of rapamycin complex 1 (mTORC1). Other downstream effects of Sestrins include autophagy activation, antiapoptotic effects in normal cells, and proapoptotic effects in cancer cells. As perturbations in the aforementioned pathways are well documented in multiple diseases, Sestrin2 might serve as a potential therapeutic target for various diseases. Thus, the aim of this review is to discuss the upstream regulators and the downstream effectors of Sestrins and to highlight the significance of Sestrin2 as a biomarker and a therapeutic target in diseases such as metabolic disorders, cardiovascular and neurodegenerative diseases, and cancer.

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“…Activation of AMPK can suppress inflammatory response and oxidative stress during OGD/R in H9c2 cells [28]. Importantly, accumulating evidence shows that Sesn2 can activate the AMPK pathway and further protect against a variety of conditions [29,30]. In this study, we found that the expression levels of p-AMPK and p-ACC were upregulated in the OGD/R group compared with the control group, whereas sufentanil treatment further enhanced the expression levels of the studied proteins ( Figure 5).…”

Section: Sufentanil Protected Against Myocardial I/r Injury In H9c2 Vmentioning

confidence: 99%

Sufentanil attenuates inflammation and oxidative stress in myocardial ischemia reperfusion injury via upregulating Sestrin 2 expression and activating AMPK signalling pathway

Jiang

Zou

et al. 2020

Biotechnology & Biotechnological Equipment

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This study explored whether sufentanil, a lipophilic opioid, can protect against myocardial ischemia-reperfusion (I/R) injury via regulating Sestrin 2 (Sesn2) expression. The expression of Sesn2 was measured in the blood of patients with myocardial I/R after sufentanil administration. H9c2 cells were applied to establish I/R injury by oxygen-glucose deprivation and reoxygenation (OGD/R). After treatment with 5, 10 and 20 lmol/L sufentanil, the expression of Sesn2 was examined. Then, shRNA-Sesn2 was transfected into H9c2 cells. The concentrations of creatine kinase (CK), CK isoenzymes (CK-MB), cardiac troponin I (cTnI), inflammation-related factors and oxidative-related factors were sequentially determined by kits. Western blotting was exploited to determine the expression of AMP-activated protein kinase (AMPK) pathway proteins. The results revealed that the expression of Sesn2 was increased in patients after administration with sufentanil. OGD/R intervention upregulated the expression of Sesn2, which continued to increase in a dose-dependent manner following treatment with sufentanil. Moreover, sufentanil attenuated the concentrations of CK, CK-MB and cTnl induced by OGD/R in H9c2 cells. This effect was reversed after Sesn2 silencing. Meanwhile, the levels of inflammatory factors and oxidative stress were notably decreased when cells were treated with sufentanil, and these inhibitory effects were alleviated after transfection with shRNA-Sesn2. Furthermore, sufentanil enhanced the phosphorylation of AMPK and its downstream acetyl CoA carboxylase (ACC), whereas Sesn2 silencing inhibited the expression of the above proteins. These findings demonstrated that sufentanil could attenuate inflammation and oxidative stress in myocardial I/R injury via upregulating Sesn2 expression and activating the AMPK pathway.

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Knockdown of sestrin2 increases pro-inflammatory reactions and ER stress in the endothelium via an AMPK dependent mechanism

Abstract: Knockdown of sesn2 aggravates atherosclerotic processes by increasing pro-inflammatory reactions and ER stress in the endothelium via an AMPK-dependent mechanism, suggesting that sesn2 might be a novel therapeutic target for atherosclerosis.

Cited by 57 publications

References 30 publications

Knockdown of Sestrin2 Increases Lipopolysaccharide-Induced Oxidative Stress, Apoptosis, and Fibrotic Reactions in H9c2 Cells and Heart Tissues of Mice via an AMPK-Dependent Mechanism

Knockdown of Sestrin2 Increases Lipopolysaccharide-Induced Oxidative Stress, Apoptosis, and Fibrotic Reactions in H9c2 Cells and Heart Tissues of Mice via an AMPK-Dependent Mechanism

Sestrin2 as a Novel Biomarker and Therapeutic Target for Various Diseases

Sufentanil attenuates inflammation and oxidative stress in myocardial ischemia reperfusion injury via upregulating Sestrin 2 expression and activating AMPK signalling pathway

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