Role of endoplasmic reticulum oxidase 1α in H9C2 cardiomyocytes following hypoxia/reoxygenation injury

Lai, Liangxue; Liu, Yue; Liu, Yuanyuan; Zhang, Ni; Cao, Shilu; Zhang, Xiaojing; Wu, Di

doi:10.3892/mmr.2020.11217

Cited by 8 publications

(5 citation statements)

References 47 publications

(44 reference statements)

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“…Therefore, Dex exerted its protective effects via the inhibition of the intrinsic pathway. Because ER stress is known to be essential for H/R‐induced apoptosis, 10 the effects of Dex on ER stress were examined. The H/R treatment induced the upregulation of GRP78 and CHOP (Figure 3I).…”

Section: Resultsmentioning

confidence: 99%

Dexmedetomidine protects cardiomyocytes against hypoxia/reoxygenation injury via multiple mechanisms

Cai

Yi-xing

Cheng

et al. 2021

Clinical Laboratory Analysis

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Background: Myocardial infarction (MI) is a serious cardiovascular disease associated with myocardial ischemia/reperfusion (I/R) injury. Dexmedetomidine (Dex), an α2adrenoceptor agonist, has been reported to protect against I/R injury. We examined the cardioprotective effects of Dex on cardiomyocytes under hypoxia/reoxygenation (H/R) conditions and explored the underlying mechanisms. Materials and methods:A H/R model was established to mimic the MI injury. The CCK-8 assay was performed to measure cell viability. Cellular apoptosis was measured using the Annexin V fluorescein isothiocyanate (FITC)-propidium iodide (PI) staining.The levels of interleukin (IL)-1α and tumor necrosis factor (TNF)α, and the activity of lactate dehydrogenase (LDH) were measured using a commercial enzyme-linked immunosorbent assay (ELISA) kit. Reactive oxygen species (ROS) were measured using the 2'-7' dichlorofluorescein diacetate (DCFH-DA) staining assay. In addition, the levels of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD), catalase (CAT), and caspase-3 were measured using a commercial kit. siRNA was used to silence Bcl-2, catalase, or STAT3. Western blotting was used to measure the change in the levels of proteins. Results: Dex improved the cell viability and inhibited the inflammatory response in H9c2 cells exposed to H/R treatment. In addition, Dex inhibited apoptosis and alleviated the endoplasmic reticulum (ER) stress and oxidative stress in H9c2 cells under the H/R treatment. Mechanism investigation showed that Dex inhibited the intrinsic pathway of apoptosis. Moreover, Dex enhanced the activation of the JAK2/ STAT3 signaling pathway in H/R-treated H9c2 cells. Conclusion: Altogether, our findings suggested Dex as a promising therapeutic agent for myocardial I/R.

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Section: Resultsmentioning

confidence: 99%

Dexmedetomidine protects cardiomyocytes against hypoxia/reoxygenation injury via multiple mechanisms

Cai

Yi-xing

Cheng

et al. 2021

Clinical Laboratory Analysis

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“…Endoplasmic reticulum oxidoreductase 1α (Ero1α), an ER-resident sulfhydryl oxidase, is responsible for catalyzing disulfide bond formation in nascent polypeptide substrates [19]. It has been found that increased Ero1α is involved in the development of ER stress-induced vascular endothelial dysfunction [20] and cardiomyopathy [21,22]. Upregulation of Ero1α exacerbates ER stress, and leads to cell death [23][24][25].…”

Section: Introductionmentioning

confidence: 99%

The regulation of Ero1-alpha in homocysteine-induced macrophage apoptosis and vulnerable plaque formation in atherosclerosis

Zhang

Zhu

et al. 2021

Atherosclerosis

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Background and aims: Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis and plaque vulnerability. Macrophage apoptosis mediated by endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of HHcy-aggravated atherosclerosis. Endoplasmic reticulum oxidoreductase 1α (Ero1α) is critical for ER stress-induced apoptosis. We hypothesized that Ero1α may contribute to ER-stress induced macrophage apoptosis and plaque stability in advanced atherosclerotic lesions by HHcy. Methods: Apoe − /− mice were maintained on drinking water containing homocysteine (Hcy, 1.8 g/L) to establish HHcy atherosclerotic models. The role of Ero1α in atherosclerotic plaque stability, macrophage apoptosis and ER stress were monitored in the plaque of aortic roots in HHcy Apoe − /− mice with or without silence or overexpression of Ero1α through lentivirus. Mouse peritoneal macrophages were used to confirm the regulation of Ero1α on ER stress dependent apoptosis in the presence of HHcy. Results: Atherosclerotic plaque vulnerability and macrophage apoptosis were promoted in Apoe − /− mice by high Hcy diet, accompanied by the upregulation of Ero1α expression and ER stress. Inhibition of Ero1α prevented macrophage apoptosis and atherosclerotic plaque vulnerability, and vice versa. Consistently, in mouse peritoneal macrophages, ER stress and apoptosis were attenuated by Ero1α deficiency, but enhanced by Ero1α overexpression. Conclusions: Hcy, via upregulation of Ero1α expression, activates ER stress-dependent macrophage apoptosis to promote vulnerable plaque formation in atherosclerosis. Ero1α may be a potential therapeutic target for atherosclerosis induced by Hcy.

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“…1B ) in a concentration-dependent manner, suggesting a modulatory effect of Dancr on cardiomyocyte ERS. Based on the finding that 2.5 µM Tm resulted in a >50% reduction in Dancr expression but maintained cell viability at ≥50%, 2.5 µM Tm was selected for subsequent experiments ( 39 ).…”

Section: Resultsmentioning

confidence: 99%

Overexpression of lncRNA Dancr inhibits apoptosis and enhances autophagy to protect cardiomyocytes from endoplasmic reticulum stress injury via sponging microRNA-6324

Xie

Wang³

et al. 2020

Mol Med Rep

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Endoplasmic reticulum stress (ERS) contributes to the pathogenesis of myocardial ischemia/reperfusion injury and myocardial infarction (MI). Long non-coding RNAs (lncRNAs) serve an important role in cardiovascular diseases, and lncRNA discrimination antagonizing non-protein coding RNA (Dancr) alleviates cardiomyocyte damage. microRNA (miR)-6324 was upregulated in MI model rats and was predicted to bind to Dancr. The present study aimed to investigate the role of Dancr in ERS-induced cardiomyocytes and the potential underlying mechanisms. Tunicamycin (Tm) was used to induce ERS. Cell viability, apoptosis and levels of associated proteins, ERS and autophagy in Dancroverexpression H9C2 cells and miR-6234 mimic-transfected H9C2 cells were assessed using Cell Counting Kit-8, TUNEL staining and western blot assay, respectively. The results suggested that Dancr expression levels and cell viability were downregulated by Tm in a concentration-dependent manner compared with the control group. Tm induced apoptosis, ERS and autophagy, as indicated by an increased ratio of apoptotic cells, increased expression levels of Bax, cleaved (c)-caspase-3/9, glucose-regulated protein 78 kDa (GRP78), phosphorylated (p)-inositol-requiring enzyme-1α (IRE1α), spliced X-box-binding protein 1 (Xbp1s), IRE1α, activating transcription factor (ATF)6, ATF4, Beclin 1 and microtubule associated protein 1 light chain 3α (LC3)II/I, and decreased expression levels of Bcl-2, unspliced Xbp1 (Xbp1u) and p62 in the Tm group compared with the control group. Moreover, the results indicated that compared with the Tm + overexpression (Oe)-negative control (NC) group, the Tm + Oe-Dancr group displayed decreased apoptosis, but enhanced ERS and autophagy to restore cellular homeostasis. Compared with the Tm + Oe-NC group, the Tm + Oe-Dancr group decreased the ratio of apoptotic cells, decreased expression levels of Bax, c-caspase-3/9 and Xbp1u, and increased expression levels of Bcl-2, p-IRE1α, Xbp1s, Beclin 1 and LC3II/I. Dancr overexpression also significantly downregulated miR-6324 expression compared with Oe-NC. The Dual-luciferase reporter assay further indicated an interaction between Dancr and miR-6324. In addition, miR-6324 mimic partially reversed the effects of Dancr overexpression on Tm-induced apoptosis, ERS and autophagy. In conclusion, lncRNA Dancr overexpression protected cardiomyocytes against ERS injury via sponging miR-6324, thus inhibiting apoptosis, enhancing autophagy and restoring ER homeostasis.

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Role of endoplasmic reticulum oxidase 1α in H9C2 cardiomyocytes following hypoxia/reoxygenation injury

Cited by 8 publications

References 47 publications

Dexmedetomidine protects cardiomyocytes against hypoxia/reoxygenation injury via multiple mechanisms

Dexmedetomidine protects cardiomyocytes against hypoxia/reoxygenation injury via multiple mechanisms

The regulation of Ero1-alpha in homocysteine-induced macrophage apoptosis and vulnerable plaque formation in atherosclerosis

Overexpression of lncRNA Dancr inhibits apoptosis and enhances autophagy to protect cardiomyocytes from endoplasmic reticulum stress injury via sponging microRNA-6324

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