Dexmedetomidine protects H9C2 against hypoxia/reoxygenation injury through miR-208b-3p/Med13/Wnt signaling pathway axis

Wang, Zhuoran; Yang, Yuqiao; Xiong, Wei; Zhou, Rui; Song, Ning; Liu, Lan; Qian, Jinqiao

doi:10.1016/j.biopha.2020.110001

Cited by 18 publications

(16 citation statements)

References 36 publications

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“…In regard to the mechanism at the cellular level, several studies have confirmed the cardioprotective effect of DEX in I/R injury based on H/R models. 23,24,41 The consistent conclusions advanced from these studies share similar outcomes with our conclusions, although the H/R models used varied among the studies. The major outcomes evaluated were cell viability, the apoptosis rate and LDH release, and by evaluating the expression of miR-208b, 23 intracellular calcium overload 24 and TLR4, 41 no ERS was found to be involved.…”

Section: Discussionsupporting

confidence: 86%

“…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. In recent years, an increasing number of basic research studies have focused on the p38MAPK signalling pathway; p38MAPK belongs to the family of MAPK-activated protein kinases and participates in many cellular processes, such as cell proliferation, survival and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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<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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Section: Discussionsupporting

confidence: 86%

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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“…Establishment of the H/R injury model. To establish an optimal in vitro H/R model, methods similar to those used by Wang et al (31) and Yuan et al (32) were used. A single-cell suspension of H9c2 cells (~5x10 5 cells/ml) was prepared and 5x10 3 cells/well were seeded in 96-well plates.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, a couple of studies have explored the function of DEX in preventing the injury of H9c2 cardiomyocytes under H/R conditions (31,32). In both studies, DEX was used to precondition the H/R H9c2 cell model, and a significant alleviation of H/R injury was achieved; the study by Wang et al (31) indicated that this was achieved through the increased expression of mediator of RNA polymerase II transcription subunit 13, while that by Yuan et al (32) demonstrated the involvement of increased FK506 binding protein 1B expression. However, the exact regulatory effect of DEX on ERS and the appropriate experimental conditions for the evaluation of its regulatory effects on H/R remain unknown.…”

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

confidence: 99%

“…Based on all of the above considerations, H9c2 cells were used in the present study to conduct experiments with exposure to hypoxia for 3 h, a duration that has previously been used by other researchers (31,42), and several reoxygenation durations were evaluated. A cell death rate of ~50% was achieved with 3 h of reoxygenation, although cell death peaked at 6 h, with a reduction of 64%.…”

Section: Dex Reduces the Expression Levels Of Grp78 Chop And Caspasementioning

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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Flavonoid Tangeretin Relieves Dysfunction in Cardiomyoblasts Undergoing Oxygen-Glucose Deprivation/Reoxygenation

Zhao

Suo

2022

Rev. Bras. Farmacogn.

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Dexmedetomidine protects H9C2 against hypoxia/reoxygenation injury through miR-208b-3p/Med13/Wnt signaling pathway axis

Cited by 18 publications

References 36 publications

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

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

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

Flavonoid Tangeretin Relieves Dysfunction in Cardiomyoblasts Undergoing Oxygen-Glucose Deprivation/Reoxygenation

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