PMID- 34279751 OWN - NLM STAT- MEDLINE DCOM- 20220930 LR - 20221002 IS - 1573-7241 (Electronic) IS - 0920-3206 (Linking) VI - 36 IP - 5 DP - 2022 Oct TI - Morphine Prevents Ischemia/Reperfusion-Induced Myocardial Mitochondrial Damage by Activating delta-opioid Receptor/EGFR/ROS Pathway. PG - 841-857 LID - 10.1007/s10557-021-07215-w [doi] AB - OBJECTIVE: The purpose of this study was to determine whether the epidermal growth factor receptor (EGFR), which is a classical receptor tyrosine kinase, is involved in the protective effect of morphine against ischemia/reperfusion (I/R)-induced myocardial mitochondrial damage. METHODS: Isolated rats hearts were subjected to global ischemia followed by reperfusion. Cardiac H9c2 cells were exposed to a simulated ischemia solution followed by Tyrode's solution to induce hypoxia/reoxygenation (H/R) injury. Triphenyltetrazolium chloride (TTC) was used to measure infarct size. The mitochondrial morphological and functional changes were determined using transmission election microscopy (TEM), mitochondrial stress assay, and mitochondrial swelling, respectively. Mitochondrial fluorescence indicator JC-1, DCFH-DA, and Mitosox Red were used to determine mitochondrial membrane potential ( big up tri, openPsim), intracellular reactive oxygen species (ROS) and mitochondrial superoxide. A TUNUL assay kit was used to detect the level of apoptosis. Western blotting analysis was used to measure the expression of proteins. RESULTS: Treatment of isolated rat hearts with morphine prevented I/R-induced myocardial mitochondrial injury, which was inhibited by the selective EGFR inhibitor AG1478, suggesting that EGFR is involved in the mitochondrial protective effect of morphine under I/R conditions. In support of this hypothesis, the selective EGFR agonist epidermal growth factor (EGF) reduced mitochondrial morphological and functional damage similarly to morphine. Further study demonstrated that morphine may alleviate I/R-induced cardiac damage by inhibiting autophagy but not apoptosis. Morphine increased protein kinase B (Akt), extracellular regulated protein kinases (ERK) and signal transducer and activator of transcription-3 (STAT-3) phosphorylation, which was inhibited by AG1478, and EGF had similar effects, indicating that morphine may activate Akt, ERK, and STAT-3 via EGFR. Morphine and EGF increased intracellular reactive oxygen species (ROS) generation. This effect of morphine was inhibited by AG1478, indicating that morphine promotes intracellular ROS generation by activating EGFR. However, morphine did not increase ROS generation when cells were transfected with siRNA against EGFR. In addition, EGFR activity was markedly increased by morphine, but the effect of morphine was reversed by naltrindole. These results suggest that morphine may activate EGFR via delta-opioid receptor activation. CONCLUSIONS: Morphine may prevent I/R-induced myocardial mitochondrial damage by activating EGFR through delta-opioid receptors, in turn increasing RISK and SAFE pathway activity via intracellular ROS. Moreover, morphine may reduce myocardial injury by regulating autophagy but not apoptosis. CI - (c) 2021. Springer Science+Business Media, LLC, part of Springer Nature. FAU - Xu, Jingman AU - Xu J AD - School of Public Health, North China University of Science and Technology, 21 Bohai Avenue, Caofeidian District, Tangshan, 063000, Hebei, China. xujm@ncst.edu.cn. FAU - Bian, Xiyun AU - Bian X AD - Central Laboratory, The Fifth Central Hospital of Tianjin, 300, Tianjin, ,450, China. FAU - Zhao, Huanhuan AU - Zhao H AD - Department of Physiology and Pathophysiology, Tianjin Medical University, 300, Tianjin, ,010, China. FAU - Sun, Yujie AU - Sun Y AD - Department of Neurology, Kailuan Hospital, Tangshan, 063000, Hebei Province, China. FAU - Tian, Yanyi AU - Tian Y AD - School of Public Health, North China University of Science and Technology, 21 Bohai Avenue, Caofeidian District, Tangshan, 063000, Hebei, China. FAU - Li, Xiaodong AU - Li X AD - School of Public Health, North China University of Science and Technology, 21 Bohai Avenue, Caofeidian District, Tangshan, 063000, Hebei, China. FAU - Tian, Wei AU - Tian W AUID- ORCID: 0000-0002-6408-5336 AD - School of Public Health, North China University of Science and Technology, 21 Bohai Avenue, Caofeidian District, Tangshan, 063000, Hebei, China. tianwei@ncst.edu.cn. LA - eng PT - Journal Article DEP - 20210719 PL - United States TA - Cardiovasc Drugs Ther JT - Cardiovascular drugs and therapy JID - 8712220 RN - 0 (Quinazolines) RN - 0 (RNA, Small Interfering) RN - 0 (Reactive Oxygen Species) RN - 0 (Receptors, Opioid) RN - 0 (Tyrphostins) RN - 11062-77-4 (Superoxides) RN - 170449-18-0 (RTKI cpd) RN - 62229-50-9 (Epidermal Growth Factor) RN - 76I7G6D29C (Morphine) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.1 (Protein-Tyrosine Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM CIN - Cardiovasc Drugs Ther. 2022 Oct;36(5):1001-1003. PMID: 35793001 MH - Animals MH - Epidermal Growth Factor/metabolism/pharmacology MH - ErbB Receptors/metabolism/pharmacology MH - Mitochondria, Heart/metabolism MH - Morphine/pharmacology MH - Myocytes, Cardiac MH - Protein-Tyrosine Kinases/metabolism/pharmacology MH - *Proto-Oncogene Proteins c-akt/metabolism MH - Quinazolines MH - RNA, Small Interfering MH - Rats MH - Reactive Oxygen Species/metabolism MH - Receptors, Opioid/metabolism MH - Reperfusion MH - *Reperfusion Injury/metabolism MH - Superoxides/metabolism/pharmacology MH - Tyrphostins OTO - NOTNLM OT - Epidermal growth factor receptor OT - Morphine OT - Reactive oxygen species OT - delta-Opioid receptor EDAT- 2021/07/20 06:00 MHDA- 2022/10/01 06:00 CRDT- 2021/07/19 13:03 PHST- 2021/06/07 00:00 [accepted] PHST- 2021/07/20 06:00 [pubmed] PHST- 2022/10/01 06:00 [medline] PHST- 2021/07/19 13:03 [entrez] AID - 10.1007/s10557-021-07215-w [pii] AID - 10.1007/s10557-021-07215-w [doi] PST - ppublish SO - Cardiovasc Drugs Ther. 2022 Oct;36(5):841-857. doi: 10.1007/s10557-021-07215-w. Epub 2021 Jul 19.