PMID- 37660968 OWN - NLM STAT- MEDLINE DCOM- 20230922 LR - 20230922 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 957 DP - 2023 Oct 15 TI - Ginsenoside Rd attenuates myocardial ischemia injury through improving mitochondrial biogenesis via WNT5A/Ca(2+) pathways. PG - 176044 LID - S0014-2999(23)00556-3 [pii] LID - 10.1016/j.ejphar.2023.176044 [doi] AB - Ginsenoside Rd, one of the main active components in ginseng, exerts various biological activities. However, its effectiveness on myocardial ischemia injury and its potential mechanism need further clarification. The model of isoproterenol (ISO)-induced myocardial ischemia injury (MI) mice and cobalt chloride (CoCl(2))-induced cardiomyocytes injury were performed. Ginsenoside Rd significantly alleviated MI injury, as evidenced by ameliorated cardiac pathological features and improved cardiac function. Simultaneously, ginsenoside Rd notably mitigated CoCl(2)-induced cell injury, decreased the lactate dehydrogenase (LDH) release and reactive oxygen species (ROS) generation in vitro. Additionally, ginsenoside Rd increased nicotinamide adenine dinucleotide (NADH) and mitochondrial membrane potential (MMP). Moreover, we found that ginsenoside Rd could increase the mitochondrial DNA (mtDNA) and promote the expression of Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1alpha), nuclear factor erythroid 2 related factor-1 (NRF1), nuclear factor erythroid 2 related factor-2 (NRF2) and activating mitochondrial transcription factor A (TFAM), which suggested that ginsenoside Rd might accelerate mitochondrial biogenesis function to ameliorate MI injury. Importantly, ginsenoside Rd treatment significantly inhibited the WNT5A/calcium (Ca(2+)) signaling pathway, decreased the expression of WNT5A, Frizzled2, phosphorylated calmodulin kinase II/calmodulin kinase II (p-CaMKII/CaMKII) and the calcium overload. Meanwhile, WNT5A siRNA was further conducted to elucidate the effect of ginsenoside Rd on CoCl(2)-induced cardiomyocyte injury. And we found that WNT5A siRNA partially weakened the protective effects of ginsenoside Rd on mitochondrial function and mitochondrial biogenesis, suggesting that ginsenoside Rd might suppress myocardial ischemia injury through WNT5A. Overall, this study demonstrated that ginsenoside Rd could alleviate myocardial ischemia injury through improving mitochondrial biogenesis via WNT5A/Ca(2+) pathways, which provided a rationale for future clinical applications and potential drugs for the treatment of cardiovascular diseases. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Cui, Zekun AU - Cui Z AD - Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China. FAU - Gu, Lifei AU - Gu L AD - NMPA Key Laboratory for Quality Research and Evaluation of Traditional Chinese Medicine, Shenzhen Institute for Drug Control, Shenzhen, China. FAU - Liu, Tao AU - Liu T AD - Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China. FAU - Liu, Yining AU - Liu Y AD - Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China. FAU - Yu, Boyang AU - Yu B AD - Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China. FAU - Kou, Junping AU - Kou J AD - Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China. FAU - Li, Fang AU - Li F AD - Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China. Electronic address: lifangcpu@163.com. FAU - Yang, Kun AU - Yang K AD - Department of Endocrinology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China; Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. Electronic address: yk_3615@sxmu.edu.cn. LA - eng PT - Journal Article DEP - 20230901 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - EVS87XF13W (cobaltous chloride) RN - WB232T95AV (ginsenoside Rd) RN - SY7Q814VUP (Calcium) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2) RN - 0 (DNA, Mitochondrial) SB - IM MH - Animals MH - Mice MH - Calcium MH - Calcium-Calmodulin-Dependent Protein Kinase Type 2 MH - Organelle Biogenesis MH - *Myocardial Ischemia/drug therapy MH - *Coronary Artery Disease MH - Ischemia MH - *Heart Injuries MH - DNA, Mitochondrial OTO - NOTNLM OT - Ginsenoside Rd OT - Myocardial ischemia OT - WNT5A OT - mitochondrial biogenesis COIS- Declaration of competing interest The authors declare no competing financial interest. EDAT- 2023/09/04 00:41 MHDA- 2023/09/22 06:42 CRDT- 2023/09/03 19:29 PHST- 2023/04/24 00:00 [received] PHST- 2023/08/30 00:00 [revised] PHST- 2023/08/31 00:00 [accepted] PHST- 2023/09/22 06:42 [medline] PHST- 2023/09/04 00:41 [pubmed] PHST- 2023/09/03 19:29 [entrez] AID - S0014-2999(23)00556-3 [pii] AID - 10.1016/j.ejphar.2023.176044 [doi] PST - ppublish SO - Eur J Pharmacol. 2023 Oct 15;957:176044. doi: 10.1016/j.ejphar.2023.176044. Epub 2023 Sep 1.