Dexmedetomidine Attenuates Myocardial Ischemia-Reperfusion Injury in Diabetes Mellitus by Inhibiting Endoplasmic Reticulum Stress

Li, Jinjie; Zhao, Ying; Zhou, Nan; Li, Longyun; Li, Kai

doi:10.1155/2019/7869318

Cited by 35 publications

(42 citation statements)

References 51 publications

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“…In previous studies, DEX exhibited a protective role in the hearts of diabetic mice by interfering with ERS or autophagy, thereby suppressing IRI (6,23); however, the results were partially attributed to the diabetes context. Furthermore, researchers have focused on the study of cells other than cardiomyocytes, such as endothelial cells, under IRI or hypoxia/reoxygenation (H/R) conditions (24,25), and have examined several crucial ERS chaperones, proteins and apoptosis indicators that are produced by organs other than the heart under IRI or H/R conditions (6,(26)(27)(28)(29)(30). These studies have shown that DEX effectively regulates the function of non-cardiomyocytes and interferes with the ERS signaling pathway under these conditions.…”

Section: Dexmedetomidine At a Dose Of 1 µM Attenuates H9c2 Cardiomyocmentioning

confidence: 85%

“…Myocardial ischemia-reperfusion injury (MIRI), which usually occurs in clinical settings, leads to severe outcomes for patients if no effective strategies are applied to inhibit the downstream apoptotic cascades. However, numerous animal studies that have revealed various protective mechanisms have also confirmed the efficacy of cardioprotection in overcoming MIRI (1)(2)(3)(4)(5)(6). However, the results achieved in the clinical application of these strategies have not been consistent with those achieved in experimental research (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

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Dexmedetomidine at a dose of 1 µM attenuates H9c2 cardiomyocyte injury under 3 h of hypoxia exposure and 3 h of reoxygenation through the inhibition of endoplasmic reticulum stress

et al. 2020

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Myocardial ischemia-reperfusion injury (MIRI) has been confirmed to induce endoplasmic reticulum stress (ERS) during downstream cascade reactions after the sufficient deterioration of cardiomyocyte function. However, clinically outcomes have been inconsistent with experimental findings because the mechanism has not been entirely elucidated. Dexmedetomidine (DEX), an α 2 adrenergic receptor agonist with anti-inflammatory and organ-protective activity, has been shown to attenuate IRI in the heart. The present study aimed to determine whether DEX is able to protect injured cardiomyocytes under in vitro hypoxia/reoxygenation (H/R) conditions and evaluate the conditions under which ERS is efficiently ameliorated. The cytotoxicity of DEX in H9c2 cells was evaluated 24 h after treatment with several different concentrations of DEX. The most appropriate H/R model parameters were determined by the assessment of cell viability and injury with Cell Counting Kit-8 and lactate dehydrogenase (LDH) release assays after incubation under hypoxic conditions for 3 h and reoxygenation conditions for 3, 6, 12 and 24 h. Additionally, the aforementioned methods were used to assess cardiomyocytes cultured with various concentrations of DEX under H/R conditions. Furthermore, the degree of apoptosis and the mRNA and protein expression levels of glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and caspase-12 were evaluated in all groups. The addition of 1, 5 and 10 µM DEX to the cell culture significantly increased the proliferation of H9c2 cells by >80% under normal culture conditions. In the H/R model assessment, following 3 h of anoxia exposure, H9c2 cell viability decreased to 62.67% with 3 h of reoxygenation and to 36% with 6 h of reoxygenation compared with the control. The viability of H9c2 cells subjected to hypoxia for 3 h and reoxygenation for 3 h increased by 61.3% when pretreated with 1 µM DEX, and the LDH concentration in the supernatant was effectively decreased by 13.7%. H/R significantly increased the percentage of apoptotic cells, as detected by flow cytometry, and increased the expression levels of GRP78, CHOP and caspase-12, while treatment with either DEX or 4-phenylbutyric acid (4-PBA) significantly attenuated these effects. Additionally, despite the protective effect of DEX against H/R injury, 4-PBA attenuated the changes induced by DEX and H/R. In conclusion, treatment with 1 µM DEX alleviated cell injury, apoptosis and the increases in GRP78, CHOP and caspase-12 expression levels in H9c2 cells induced by 3 h of hypoxia and 3 h of reoxygenation.

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Section: Dexmedetomidine At a Dose Of 1 µM Attenuates H9c2 Cardiomyocmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Dexmedetomidine at a dose of 1 µM attenuates H9c2 cardiomyocyte injury under 3 h of hypoxia exposure and 3 h of reoxygenation through the inhibition of endoplasmic reticulum stress

et al. 2020

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“…Judging from existing studies, DEX performs a protective role in inhibiting IRI in the heart of diabetic mice by interfering with ERS or autophagy; 6,15 however, these results were partly attributed to the diabetes context. Furthermore, researchers have focused on studying other non-cardiac cells, such as endothelial cells, under IRI or H/R conditions 16,17 and examining several crucial ERS chaperones, proteins and apoptosis indicators produced by organs other than the heart under IRI or H/R conditions, 6,[18][19][20][21][22] finding that DEX can effectively regulate the function of non-cardiac cells and interfere in the endoplasmic reticulum stress signalling pathway under certain circumstances. Few studies have explored the function of DEX in H9c2 cardiomyocytes under H/R conditions; 23,24 however, the exact regulatory effect of DEX on ERS remains unknown.…”

Section: Introductionmentioning

confidence: 95%

“…Fortunately, numerous animal studies evaluating diverse protective mechanisms have confirmed the efficacy of cardioprotection in ameliorating MIRI. [1][2][3][4][5][6] The actual clinical application of some of these strategies, however, does not match the animal study applications, and it is difficult to predict the consequences in clinical practice from those seen in experimental research. [7][8][9] In this context, the unclear mechanism underlying the development of apoptotic pathways or involving key molecules in MIRI might significantly matter, especially for cell death and even associated signalling pathways during ischaemia-reperfusion, such as ERS-related apoptosis or signalling pathways; a noteworthy report by Davidson in 2019 shared the opinion that multitarget strategies must be adopted to reduce MIRI if appropriate because single approaches have a limited capacity to overcome complicated MIRI situations.…”

Section: Introductionmentioning

confidence: 99%

<p>Dexmedetomidine Attenuates Cellular Injury and Apoptosis in H9c2 Cardiomyocytes by Regulating p-38MAPK and Endoplasmic Reticulum Stress</p>

Zhu

Ling

Zhou

et al. 2020

DDDT

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Background: Myocardial ischaemia-reperfusion injury (IRI) has been confirmed to induce endoplasmic reticulum stress (ERS) when myocardial cell function continues to deteriorate to a certain degree. The clinical applications of effective tested strategies are sometimes inconsistent with the applications evaluated in experiments, although reasonable mechanisms and diverse signalling pathways have been broadly explored. Dexmedetomidine (DEX) has been shown to attenuate IRI of the heart in animal studies. This study aimed to determine whether DEX can protect injured cardiomyocytes under hypoxia/reoxygenation (H/R) at the cellular level and whether the mechanism is related to ERS and the p38 MAPK pathway. Methods: H9c2 cells were subjected to H/R or thapsigargin (TG) to build a model. DEX or 4-PBA was added to the medium either 1 h or 24 h before modelling, respectively. Model parameters were determined by assessing cell viability and injury, which were measured by assessing cell counting kit-8 (CCK8), lactate dehydrogenase (LDH) release and flow cytometry results, and the expression of GRP78, CHOP and caspase-12. In addition, the protein expression of p38MAPK and p-p38MAPK was examined, and SB202190, a negative regulator, was also preincubated in medium. Results: Compared to that of cells in the control group, the activity of cells in the H/R and TG groups was decreased dramatically, and the LDH concentration and proportion of apoptotic cells were increased. DEX could correspondingly reverse the changes induced by H/R or TG. Additionally, DEX effectively attenuated ERS defined as increased expression of GRP78, CHOP and caspase-12. Additionally, DEX could obviously depress the P38 MAPK phosphorylation and high p-p38 MAPK expression in the TG group, indicating DEX has a function similar to that of SB202190. Conclusion: H/R injury in H9c2 cells can lead to abnormal ERS and apoptosis, as well as activation of the p38MAPK signalling pathway. DEX can protect cardiomyocytes by intervening in ERS, regulating p38MAPK and the downstream apoptotic signalling pathway.

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“…But excessive ER stress induces apoptosis 7 . Previous studies revealed that ER stress–initiated apoptosis plays a very important role in MI/R injury 8 , 9 . Therefore, ER stress, as a potential target for the treatment of I/R-induced myocardial injury, has been an area of extensive research.…”

Section: Introductionmentioning

confidence: 99%

Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stromal Cells Protect Cardiac Cells Against Hypoxia/Reoxygenation Injury by Inhibiting Endoplasmic Reticulum Stress via Activation of the PI3K/Akt Pathway

et al. 2020

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Endoplasmic reticulum (ER) stress is implicated in the pathogenesis of many diseases, including myocardial ischemia/reperfusion injury. We hypothesized that human umbilical cord mesenchymal stromal cells derived extracellular vesicles (HuMSC-EVs) could protect cardiac cells against hyperactive ER stress induced by hypoxia/reoxygenation (H/R) injury. The H/R model was generated using the H9c2 cultured cardiac cell line. HuMSC-EVs were extracted using a commercially available exosome isolation reagent. Levels of apoptosis-related signaling molecules and the degree of ER stress were assessed by western blot. The role of the PI3K/Akt pathway was investigated using signaling inhibitors. Lactate dehydrogenase leakage and 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) analysis were used for evaluating the therapeutic effects of HuMSC-EVs in vitro. The results showed that ER stress and the rate of apoptosis were increased in the context of H/R injury. Treatment with HuMSC-EVs inhibited ER stress and increased survival in H9c2 cells exposed to H/R. Mechanistically, the PI3K/Akt pathway was activated by treatment with HuMSC-EVs after H/R. Inhibition of the PI3K/Akt pathway by a specific inhibitor, LY294002, partially reduced the protective effect of HuMSC-EVs. Our findings suggest that HuMSC-EVs could alleviate ER stress–induced apoptosis during H/R via activation of the PI3K/Akt pathway.

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Dexmedetomidine Attenuates Myocardial Ischemia-Reperfusion Injury in Diabetes Mellitus by Inhibiting Endoplasmic Reticulum Stress

Cited by 35 publications

References 51 publications

Dexmedetomidine at a dose of 1 µM attenuates H9c2 cardiomyocyte injury under 3 h of hypoxia exposure and 3 h of reoxygenation through the inhibition of endoplasmic reticulum stress

Dexmedetomidine at a dose of 1 µM attenuates H9c2 cardiomyocyte injury under 3 h of hypoxia exposure and 3 h of reoxygenation through the inhibition of endoplasmic reticulum stress

<p>Dexmedetomidine Attenuates Cellular Injury and Apoptosis in H9c2 Cardiomyocytes by Regulating p-38MAPK and Endoplasmic Reticulum Stress</p>

Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stromal Cells Protect Cardiac Cells Against Hypoxia/Reoxygenation Injury by Inhibiting Endoplasmic Reticulum Stress via Activation of the PI3K/Akt Pathway

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