PMID- 36529277 OWN - NLM STAT- MEDLINE DCOM- 20230117 LR - 20230117 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 940 DP - 2023 Feb 5 TI - Emodin protects against homocysteine-induced cardiac dysfunction by inhibiting oxidative stress via MAPK and Akt/eNOS/NO signaling pathways. PG - 175452 LID - S0014-2999(22)00713-0 [pii] LID - 10.1016/j.ejphar.2022.175452 [doi] AB - Elevated levels of plasma homocysteine (Hcy) causes severe cardiac dysfunction, which is closely associated with oxidative stress. Emodin, a naturally occurring anthraquinone derivative, has been shown to exert antioxidant and anti-apoptosis activities. However, whether emodin could protect against Hcy-induced cardiac dysfunction remains unknown. The current study aimed to investigate the effects of emodin on the Hcy-induced cardiac dysfunction and its molecular mechanisms. Rats were fed a methionine diet to establish the animal model of hyperhomocysteinemia (HHcy). H9C2 cells were incubated with Hcy to induce a cell model of Hcy-injured cardiomyocytes. ELISA, HE staining, carotid artery and left ventricular cannulation, MTT, fluorescence staining, flow cytometry and western blotting were used in this study. Emodin significantly alleviated the structural damage of the myocardium and cardiac dysfunction from HHcy rats. Emodin prevented apoptosis and the collapse of MMP in the Hcy-treated H9C2 cells in vitro. Further, emodin reversed the Hcy-induced apoptosis-related biochemical changes including decreased Bcl-2/Bax protein ratio, and increased protein expression of Caspase-9/3. Moreover, emodin suppressed oxidative stress in Hcy-treated H9C2 cells. Mechanistically, emodin significantly inhibited the Hcy-activated MAPK by reducing ROS generation in H9C2 cells. Furthermore, emodin upregulated NO production by promoting the protein phosphorylation of Akt and eNOS in injured cells. The present study shows that emodin protects against Hcy-induced cardiac dysfunction by inhibiting oxidative stress via MAPK and Akt/eNOS/NO signaling pathways. CI - Copyright (c) 2022 Elsevier B.V. All rights reserved. FAU - Liu, Ya-Ping AU - Liu YP AD - School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, 271016, China. FAU - Zhou, Guang Hai AU - Zhou GH AD - Department of Central Laboratory, Second Affiliated Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, 271000, China; College of Clinical and Basic Medical Sciences & Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250000, China. FAU - Song, Xin AU - Song X AD - School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, 271016, China. FAU - Wang, Yu-Hao AU - Wang YH AD - School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, 271016, China. FAU - Zhang, Feng AU - Zhang F AD - Department of Central Laboratory, Second Affiliated Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, 271000, China; College of Clinical and Basic Medical Sciences & Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250000, China. FAU - Chen, Qi-Qi AU - Chen QQ AD - School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, 271016, China. FAU - Cho, Kyung Woo AU - Cho KW AD - Department of Central Laboratory, Second Affiliated Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, 271000, China; College of Clinical and Basic Medical Sciences & Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250000, China. FAU - Jin, Song Nan AU - Jin SN AD - School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, 271016, China. Electronic address: snjin@sdfmu.edu.cn. FAU - Wen, Jin Fu AU - Wen JF AD - Department of Central Laboratory, Second Affiliated Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, 271000, China; College of Clinical and Basic Medical Sciences & Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250000, China. Electronic address: jfwen@sdfmu.edu.cn. LA - eng PT - Journal Article DEP - 20221215 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - KA46RNI6HN (Emodin) RN - 0 (Antioxidants) RN - 0LVT1QZ0BA (Homocysteine) SB - IM MH - Rats MH - Animals MH - *Proto-Oncogene Proteins c-akt/metabolism MH - *Emodin/pharmacology MH - Oxidative Stress MH - Signal Transduction MH - Antioxidants/pharmacology MH - Homocysteine/metabolism OTO - NOTNLM OT - Cardiac dysfunction OT - Emodin OT - Homocysteine OT - MAPK OT - Nitric oxide OT - Oxidative stress COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2022/12/19 06:00 MHDA- 2023/01/18 06:00 CRDT- 2022/12/18 19:23 PHST- 2022/09/07 00:00 [received] PHST- 2022/11/23 00:00 [revised] PHST- 2022/12/08 00:00 [accepted] PHST- 2022/12/19 06:00 [pubmed] PHST- 2023/01/18 06:00 [medline] PHST- 2022/12/18 19:23 [entrez] AID - S0014-2999(22)00713-0 [pii] AID - 10.1016/j.ejphar.2022.175452 [doi] PST - ppublish SO - Eur J Pharmacol. 2023 Feb 5;940:175452. doi: 10.1016/j.ejphar.2022.175452. Epub 2022 Dec 15.