PMID- 34555398 OWN - NLM STAT- MEDLINE DCOM- 20220204 LR - 20220204 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 911 DP - 2021 Nov 15 TI - Cardio-protective effect of tetrahydrocurcumin, the primary hydrogenated metabolite of curcumin in vivo and in vitro: Induction of apoptosis and autophagy via PI3K/AKT/mTOR pathways. PG - 174495 LID - S0014-2999(21)00649-X [pii] LID - 10.1016/j.ejphar.2021.174495 [doi] AB - Tetrahydrocurcumin (THC) is an essential metabolite of curcumin, a major active component of the Curcuma species, which have been used traditionally for the treatment of cardiovascular diseases. The PI3K/AKT/mTOR signaling pathways serve a vital role during myocardial ischemia-reperfusion (MI/R) injury. The aim of the present study was to investigate the cardioprotective potential and mechanism of THC. In the in vivo study, an animal model of MI/R was induced by coronary occlusion. Results indicated that THC (50 mg/kg/day) protected the rat hearts from MI/R-induced heart failure by increasing ejection fraction (EF) and fractional shortening (FS) and decreasing left ventricular end systolic diameter (LVESD) and left ventricular end systolic volume (LVESV). THC also reduced myocardial infarct size and apoptosis. Furthermore, H9c2 cells were incubated with THC (20 muM) to explore its potential effect following exposure to hypoxia and reoxygenation (H/R). THC post-treatment significantly augmented cell viability and prevented lactate dehydrogenase (LDH) release after H/R exposure. THC effectively improved antioxidant activity by increasing SOD and CAT activities and decreasing MDA level. THC also enhanced mitochondrial membrane potential, inhibited apoptotic cell death, diminished the Bax/Bcl-2 ratio and cleaved caspase-3 level relative to the H/R model. In addition, THC effectively decreased Beclin1 expression and LC3 II/LC3 I ratio, but increased p62 expression, compared with the H/R model group, and decreased the formation of H/R-induced autophagosomes and autolysosomes. Furthermore, THC promoted the phosphorylation of PI3K/AKT/mTOR and induced the expression of hypoxia-inducible factor 1alpha (HIF-1alpha) after H/R. However, these effects on H9c2 cells were notably abolished by the PI3K inhibitor LY294002 and mTOR inhibitor rapamycin. In conclusion, THC effectively inhibited H/R-induced autophagy and apoptosis via, at least partially, activating the PI3K/AKT/mTOR pathways. THC might have the potential to be further developed into a potential candidate for the treatment of MI/R injury. CI - Copyright (c) 2021 Elsevier B.V. All rights reserved. FAU - Chen, Xiaoying AU - Chen X AD - School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, PR China. FAU - Xie, Qingfeng AU - Xie Q AD - Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, PR China; The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, PR China. FAU - Zhu, Ying AU - Zhu Y AD - The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, PR China. FAU - Xu, Jiamin AU - Xu J AD - The Second School of Medicine, Guangzhou University of Chinese Medicine, Guangzhou, PR China. FAU - Lin, Guoshu AU - Lin G AD - School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, PR China. FAU - Liu, Shujun AU - Liu S AD - The Second School of Medicine, Guangzhou University of Chinese Medicine, Guangzhou, PR China. FAU - Su, Ziren AU - Su Z AD - School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, PR China; Dongguan Institute of Guangzhou University of Chinese Medicine, Dongguan, PR China. FAU - Lai, Xiaoping AU - Lai X AD - School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, PR China; Dongguan Institute of Guangzhou University of Chinese Medicine, Dongguan, PR China. Electronic address: lxp88@gzucm.edu.cn. FAU - Li, Qian AU - Li Q AD - The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, PR China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, PR China. FAU - Xie, Jianhui AU - Xie J AD - The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, PR China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, PR China. FAU - Yang, Xiaobo AU - Yang X AD - The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, PR China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, PR China. Electronic address: yangxiaobo39358517@hotmail.com. LA - eng PT - Journal Article DEP - 20210920 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 SB - IM MH - *Phosphatidylinositol 3-Kinases OTO - NOTNLM OT - Apoptosis OT - Autophagy OT - Hypoxia/reoxygenation OT - Ischemia-reperfusion OT - PI3K/AKT/mTOR OT - Tetrahydrocurcumin EDAT- 2021/09/24 06:00 MHDA- 2022/02/05 06:00 CRDT- 2021/09/23 20:12 PHST- 2021/06/14 00:00 [received] PHST- 2021/08/14 00:00 [revised] PHST- 2021/09/06 00:00 [accepted] PHST- 2021/09/24 06:00 [pubmed] PHST- 2022/02/05 06:00 [medline] PHST- 2021/09/23 20:12 [entrez] AID - S0014-2999(21)00649-X [pii] AID - 10.1016/j.ejphar.2021.174495 [doi] PST - ppublish SO - Eur J Pharmacol. 2021 Nov 15;911:174495. doi: 10.1016/j.ejphar.2021.174495. Epub 2021 Sep 20.