PMID- 33116411 OWN - NLM STAT- MEDLINE DCOM- 20210806 LR - 20220417 IS - 1177-8881 (Electronic) IS - 1177-8881 (Linking) VI - 14 DP - 2020 TI - Dexmedetomidine Attenuates Cellular Injury and Apoptosis in H9c2 Cardiomyocytes by Regulating p-38MAPK and Endoplasmic Reticulum Stress. PG - 4231-4243 LID - 10.2147/DDDT.S265970 [doi] AB - 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 fl ow 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. CI - (c) 2020 Zhu et al. FAU - Zhu, Zhipeng AU - Zhu Z AUID- ORCID: 0000-0001-5575-3833 AD - Department of Anesthesiology, The Second Affiliated Hospital of Jiaxing University, Jiaxing City, Zhejiang Province 314000, People's Republic of China. FAU - Ling, Xiaoyan AU - Ling X AD - The Outpatient Nursing Department of the Second Affiliated Hospital of Jiaxing University, Jiaxing City, Zhejiang Province 314000, People's Republic of China. FAU - Zhou, Hongmei AU - Zhou H AD - Department of Anesthesiology, The Second Affiliated Hospital of Jiaxing University, Jiaxing City, Zhejiang Province 314000, People's Republic of China. FAU - Zhang, Caijun AU - Zhang C AD - Department of Anesthesiology, The Second Affiliated Hospital of Jiaxing University, Jiaxing City, Zhejiang Province 314000, People's Republic of China. FAU - Yan, Weiwei AU - Yan W AD - Department of Anesthesiology, The Second Affiliated Hospital of Jiaxing University, Jiaxing City, Zhejiang Province 314000, People's Republic of China. LA - eng PT - Journal Article DEP - 20201012 PL - New Zealand TA - Drug Des Devel Ther JT - Drug design, development and therapy JID - 101475745 RN - 0 (Hypnotics and Sedatives) RN - 0 (Imidazoles) RN - 0 (Pyridines) RN - 67526-95-8 (Thapsigargin) RN - 67VB76HONO (Dexmedetomidine) RN - EC 1.1.1.27 (L-Lactate Dehydrogenase) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - PVX798P8GI (4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole) SB - IM MH - Animals MH - Apoptosis/*drug effects MH - Cell Hypoxia MH - Cell Line MH - Cell Survival/drug effects MH - Dexmedetomidine/*pharmacology MH - Endoplasmic Reticulum Stress/*drug effects MH - Hypnotics and Sedatives/*pharmacology MH - Imidazoles/pharmacology MH - L-Lactate Dehydrogenase/metabolism MH - Myocardial Reperfusion Injury MH - Myocytes, Cardiac/*drug effects MH - Pyridines/pharmacology MH - Rats MH - Signal Transduction/drug effects MH - Thapsigargin/pharmacology MH - p38 Mitogen-Activated Protein Kinases/drug effects/*metabolism PMC - PMC7568428 OTO - NOTNLM OT - dexmedetomidine OT - endoplasmic reticulum stress signalling pathway OT - hypoxia/reoxygenation injury OT - p38 mitogen-activated protein kinase COIS- The authors report no con fl ict of interest related to this paper. EDAT- 2020/10/30 06:00 MHDA- 2021/08/07 06:00 PMCR- 2020/10/12 CRDT- 2020/10/29 05:48 PHST- 2020/06/03 00:00 [received] PHST- 2020/09/19 00:00 [accepted] PHST- 2020/10/29 05:48 [entrez] PHST- 2020/10/30 06:00 [pubmed] PHST- 2021/08/07 06:00 [medline] PHST- 2020/10/12 00:00 [pmc-release] AID - 265970 [pii] AID - 10.2147/DDDT.S265970 [doi] PST - epublish SO - Drug Des Devel Ther. 2020 Oct 12;14:4231-4243. doi: 10.2147/DDDT.S265970. eCollection 2020.