Curcumin pretreatment attenuates myocardial ischemia/reperfusion injury by inhibiting ferroptosis, autophagy and apoptosis via HES1

Yuan,Yong; Huang,Huang; Hu,Tie; Zou,Chenchao; Qiao,Yamei; Fang,Ming; Liu,Jichun; Lai,Songqing

doi:10.3892/ijmm.2024.5434

Curcumin pretreatment attenuates myocardial ischemia/reperfusion injury by inhibiting ferroptosis, autophagy and apoptosis via HES1

Authors:
- Yong Yuan
- Huang Huang
- Tie Hu
- Chenchao Zou
- Yamei Qiao
- Ming Fang
- Jichun Liu
- Songqing Lai
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Affiliations: Department of Cardiovascular Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Cardiovascular Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Cardiovascular Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Jiangxi Provincial Key Laboratory of Basic Pharmacology, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Emergency, Gaoxin Branch of The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Cardiovascular Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
Published online on: October 1, 2024 https://doi.org/10.3892/ijmm.2024.5434
Article Number: 110
Copyright: © Yuan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The early restoration of hemodynamics/reperfusion in acute myocardial infarction (AMI) is an effective therapeutic strategy to reduce sudden death and improve patient prognosis. However, reperfusion induces additional cardiomyocyte damage and cardiac tissue dysfunction. In this context, turmeric‑derived curcumin (Cur) has been shown to exhibit a protective effect against myocardial ischemia/reperfusion injury (I/RI). The molecular mechanism of its activity, however, remains unclear. The current study investigated the protective effect of Cur and its molecular mechanism via in vitro experiments. The Cell Counting Kit‑8 and lactate dehydrogenase (LDH) assay kit were used to assess the cell viability and cytotoxicity. The contents of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase, glutathione (GSH)/glutathione disulfide (GSSG), total iron, ferrous iron, caspase‑3 and reactive oxygen species (ROS) were measured using an appropriate kit. Western blotting was used to detect the expression of relevant proteins. The levels of apoptosis, mitochondrial permeability transition pore (MPTP) opening, and mitochondrial membrane potential (MMP) were detected by flow cytometry. The study findings indicated that anoxia/reoxygenation (A/R) injury significantly decreased cell viability, increased in LDH and caspase‑3 activities, induced ferroptosis, increased apoptosis and overactivated autophagy. However, pretreatment with Cur or ferrostatin‑1 (Fer‑1, a ferroptosis inhibitor) significantly increased A/R‑reduced cell viability, SOD, glutathione peroxidase activity, GSH/GSSH ratio and HES1 and glutathione peroxidase 4 protein expression; attenuated A/R‑induced LDH, MDA, total iron, ferrous iron, prostaglandin‑endoperoxide synthase 2 protein expression and prevented ROS overproduction and MMP loss. In addition, Cur inhibited caspase‑3 activity, upregulated the Bcl‑2/Bax ratio, reduced apoptotic cell number and inhibited MPTP over‑opening. Furthermore, Cur increased P62, LC3II/I, NDUFB8 and UQCRC2 expression and upregulated the p‑AMPK/AMPK ratio. However, erastin (a ferroptosis activator), pAD/HES1‑short hairpin RNA, rapamycin (an autophagy activator) and Compound C (an AMPK inhibitor) blocked the protective effect of Cur. In conclusion, Cur pretreatment inhibited ferroptosis, autophagy overactivation and oxidative stress; improved mitochondrial dysfunction; maintained energy homeostasis; attenuated apoptosis; and ultimately protected the myocardium from A/R injury via increased HES1 expression.

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1	Anderson JL and Morrow DA: Acute myocardial infarction. N Engl J Med. 376:2053–2064. 2017. View Article : Google Scholar : PubMed/NCBI
2	Algoet M, Janssens S, Himmelreich U, Gsell W, Pusovnik M, Van den Eynde J and Oosterlinck W: Myocardial ischemia-reperfusion injury and the influence of inflammation. Trends Cardiovasc Med. 33:357–366. 2023. View Article : Google Scholar
3	Salari N, Morddarvanjoghi F, Abdolmaleki A, Rasoulpoor S, Khaleghi AA, Hezarkhani LA, Shohaimi S and Mohammadi M: The global prevalence of myocardial infarction: A systematic review and meta-analysis. BMC Cardiovasc Disord. 23:2062023. View Article : Google Scholar : PubMed/NCBI
4	Martí-Pàmies Í, Thoonen R, Morley M, Graves L, Tamez J, Caplan A, McDaid K, Yao V, Hindle A, Gerszten RE, et al: Brown adipose tissue and BMP3b decrease injury in cardiac ischemia-reperfusion. Circ Res. 133:353–365. 2023. View Article : Google Scholar : PubMed/NCBI
5	Xue Y, Fu W, Yu P, Li Y, Yu X, Xu H and Sui D: Ginsenoside Rc alleviates myocardial ischemia-reperfusion injury by reducing mitochondrial oxidative stress and apoptosis: Role of SIRT1 activation. J Agric Food Chem. 71:1547–1561. 2023. View Article : Google Scholar : PubMed/NCBI
6	Gu S, Tan J, Li Q, Liu S, Ma J, Zheng Y, Liu J, Bi W, Sha P, Li X, et al: Downregulation of LAPTM4B contributes to the impairment of the autophagic flux via unopposed activation of mTORC1 signaling during myocardial ischemia/reperfusion injury. Circ Res. 127:e148–e165. 2020. View Article : Google Scholar : PubMed/NCBI
7	Cai W, Liu L, Shi X, Liu Y, Wang J, Fang X, Chen Z, Ai D, Zhu Y and Zhang X: Alox15/15-HpETE aggravates myocardial ischemia-reperfusion injury by promoting cardiomyocyte ferroptosis. Circulation. 147:1444–1460. 2023. View Article : Google Scholar : PubMed/NCBI
8	Del Re DP, Amgalan D, Linkermann A, Liu Q and Kitsis RN: Fundamental mechanisms of regulated cell death and implications for heart disease. Physiol Rev. 99:1765–1817. 2019. View Article : Google Scholar : PubMed/NCBI
9	Sciarretta S, Maejima Y, Zablocki D and Sadoshima J: The role of autophagy in the heart. Annu Rev Physiol. 80:1–26. 2018. View Article : Google Scholar
10	Chen X, Xie Q, Zhu Y, Xu J, Lin G, Liu S, Su Z, Lai X, Li Q, Xie J, et al: 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. Eur J Pharmacol. 911:1744952021. View Article : Google Scholar : PubMed/NCBI
11	Steinberg GR and Hardie DG: New insights into activation and function of the AMPK. Nat Rev Mol Cell Biol. 24:255–272. 2023. View Article : Google Scholar
12	Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, et al: Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell. 149:1060–1072. 2012. View Article : Google Scholar : PubMed/NCBI
13	Fang X, Ardehali H, Min J and Wang F: The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease. Nat Rev Cardiol. 20:7–23. 2023. View Article : Google Scholar
14	Xing G, Meng L, Cao S, Liu S, Wu J, Li Q, Huang W and Zhang L: PPARα alleviates iron overload-induced ferroptosis in mouse liver. EMBO Rep. 23:e522802022. View Article : Google Scholar
15	Hu T, Zou HX, Le SY, Wang YR, Qiao YM, Yuan Y, Liu JC, Lai SQ and Huang H: Tanshinone IIA confers protection against myocardial ischemia/reperfusion injury by inhibiting ferroptosis and apoptosis via VDAC1. Int J Mol Med. 52:109 [pii]2023. View Article : Google Scholar : PubMed/NCBI
16	Liu B, Zhao C, Li H, Chen X, Ding Y and Xu S: Puerarin protects against heart failure induced by pressure overload through mitigation of ferroptosis. Biochem Biophys Res Commun. 497:233–240. 2018. View Article : Google Scholar : PubMed/NCBI
17	Cao JF, Gong Y, Wu M, Xiong L, Chen S, Huang H, Zhou X, Peng YC, Shen XF, Qu J, et al: Molecular docking and molecular dynamics study Lianhua Qingwen granules (LHQW) treats COVID-19 by inhibiting inflammatory response and regulating cell survival. Front Cell Infect Microbiol. 12:10447702022. View Article : Google Scholar : PubMed/NCBI
18	Poespoprodjo JR, Douglas NM, Ansong D, Kho S and Anstey NM: Malaria. Lancet. 402:2328–2345. 2023. View Article : Google Scholar : PubMed/NCBI
19	Wang ZK, Chen RR, Li JH, Chen JY, Li W, Niu XL, Wang FF, Wang J and Yang JX: Puerarin protects against myocardial ischemia/reperfusion injury by inhibiting inflammation and the NLRP3 inflammasome: The role of the SIRT1/NF-κB pathway. Int Immunopharmacol. 89:1070862020. View Article : Google Scholar
20	Duan W, Yang Y, Yan J, Yu S, Liu J, Zhou J, Zhang J, Jin Z and Yi D: The effects of curcumin post-treatment against myocardial ischemia and reperfusion by activation of the JAK2/STAT3 signaling pathway. Basic Res Cardiol. 107:2632012. View Article : Google Scholar : PubMed/NCBI
21	Zhu P, Yang M, He H, Kuang Z, Liang M, Lin A, Liang S, Wen Q, Cheng Z and Sun C: Curcumin attenuates hypoxia/reoxygenation-induced cardiomyocyte injury by downregulating Notch signaling. Mol Med Rep. 20:1541–1550. 2019.PubMed/NCBI
22	Huang H, Lai S, Wan Q, Qi W and Liu J: Astragaloside IV protects cardiomyocytes from anoxia/reoxygenation injury by upregulating the expression of Hes1 protein. Can J Physiol Pharmacol. 94:542–553. 2016. View Article : Google Scholar : PubMed/NCBI
23	Yu L, Li F, Zhao G, Yang Y, Jin Z, Zhai M, Yu W, Zhao L, Chen W, Duan W, et al: Protective effect of berberine against myocardial ischemia reperfusion injury: role of Notch1/Hes1-PTEN/Akt signaling. Apoptosis. 20:796–810. 2015. View Article : Google Scholar : PubMed/NCBI
24	Flameng W, Borgers M, Daenen W and Stalpaert G: Ultrastructural and cytochemical correlates of myocardial protection by cardiac hypothermia in man. J Thorac Cardiovasc Surg. 79:413–424. 1980. View Article : Google Scholar : PubMed/NCBI
25	Li FJ, Long HZ, Zhou ZW, Luo HY, Xu SG and Gao LC: System X(c) (-)/GSH/GPX4 axis: An important antioxidant system for the ferroptosis in drug-resistant solid tumor therapy. Front Pharmacol. 13:9102922022. View Article : Google Scholar : PubMed/NCBI
26	Cai C, Guo Z, Chang X, Li Z, Wu F, He J, Cao T, Wang K, Shi N, Zhou H, et al: Empagliflozin attenuates cardiac microvascular ischemia/reperfusion through activating the AMPKα1/ULK1/FUNDC1/mitophagy pathway. Redox Biol. 52:1022882022. View Article : Google Scholar
27	Sun Y, Yao X, Zhang QJ, Zhu M, Liu ZP, Ci B, Xie Y, Carlson D, Rothermel BA, Sun Y, et al: Beclin-1-dependent autophagy protects the heart during sepsis. Circulation. 138:2247–2262. 2018. View Article : Google Scholar : PubMed/NCBI
28	Ye T, Yang W, Gao T, Yu X, Chen T, Yang Y, Guo J, Li Q, Li H and Yang L: Trastuzumab-induced cardiomyopathy via ferroptosis-mediated mitochondrial dysfunction. Free Radic Biol Med. 206:143–161. 2023. View Article : Google Scholar : PubMed/NCBI
29	Herzig S and Shaw RJ: AMPK: Guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol. 19:121–135. 2018. View Article : Google Scholar :
30	Zhao D, Liu J, Wang M, Zhang X and Zhou M: Epidemiology of cardiovascular disease in China: Current features and implications. Nat Rev Cardiol. 16:203–212. 2019. View Article : Google Scholar
31	Sawashita Y, Hirata N, Yoshikawa Y, Terada H, Tokinaga Y and Yamakage M: Remote ischemic preconditioning reduces myocardial ischemia-reperfusion injury through unacylated ghrelin-induced activation of the JAK/STAT pathway. Basic Res Cardiol. 115:502020. View Article : Google Scholar : PubMed/NCBI
32	Wu X, Liu L, Zheng Q, Ye H, Yang H, Hao H and Li P: Dihydrotanshinone I preconditions myocardium against ischemic injury via PKM2 glutathionylation sensitive to ROS. Acta Pharm Sin B. 13:113–127. 2023. View Article : Google Scholar : PubMed/NCBI
33	Yu LM, Dong X, Xue XD, Zhang J, Li Z, Wu HJ, Yang ZL, Yang Y and Wang HS: Naringenin improves mitochondrial function and reduces cardiac damage following ischemia-reperfusion injury: the role of the AMPK-SIRT3 signaling pathway. Food Funct. 10:2752–2765. 2019. View Article : Google Scholar : PubMed/NCBI
34	Wan J, Zhang Z, Wu C, Tian S, Zang Y, Jin G, Sun Q, Wang P, Luan X, Yang Y, et al: Astragaloside IV derivative HHQ16 ameliorates infarction-induced hypertrophy and heart failure through degradation of lncRNA4012/9456. Signal Transduct Target Ther. 8:4142023. View Article : Google Scholar : PubMed/NCBI
35	Jiang C, Shi Q, Yang J, Ren H, Zhang L, Chen S, Si J, Liu Y, Sha D, Xu B and Ni J: Ceria nanozyme coordination with curcumin for treatment of sepsis-induced cardiac injury by inhibiting ferroptosis and inflammation. J Adv Res. 63:159–170. 2023. View Article : Google Scholar : PubMed/NCBI
36	Ruan Y, Xiong Y, Fang W, Yu Q, Mai Y, Cao Z, Wang K, Lei M, Xu J, Liu Y, et al: Highly sensitive curcumin-conjugated nanotheranostic platform for detecting amyloid-beta plaques by magnetic resonance imaging and reversing cognitive deficits of Alzheimer's disease via NLRP3-inhibition. J Nanobiotechnology. 20:3222022. View Article : Google Scholar : PubMed/NCBI
37	Wang X, Zhang Y, Yang Y, Zhang W, Luo L, Han F, Guan H, Tao K and Hu D: Curcumin pretreatment protects against hypoxia/reoxgenation injury via improvement of mitochondrial function, destabilization of HIF-1α and activation of Epac1-Akt pathway in rat bone marrow mesenchymal stem cells. Biomed Pharmacother. 109:1268–1275. 2019. View Article : Google Scholar
38	Kim YS, Kwon JS, Cho YK, Jeong MH, Cho JG, Park JC, Kang JC and Ahn Y: Curcumin reduces the cardiac ischemia-reperfusion injury: Involvement of the toll-like receptor 2 in cardiomyocytes. J Nutr Biochem. 23:1514–1523. 2012. View Article : Google Scholar : PubMed/NCBI
39	Bo H and Feng X: Post-treatment curcumin reduced ischemia-reperfusion-induced pulmonary injury via the Notch2/Hes-1 pathway. J Int Med Res. 48:3000605198924322020. View Article : Google Scholar : PubMed/NCBI
40	Zhang M, Yu LM, Zhao H, Zhou XX, Yang Q, Song F, Yan L, Zhai ME, Li BY, Zhang B, et al: 2,3,5,4′-Tetrahydroxystilbe ne-2-O-β-D-glucoside protects murine hearts against ischemia/reperfusion injury by activating Notch1/Hes1 signaling and attenuating endoplasmic reticulum stress. Acta Pharmacol Sin. 38:317–330. 2017. View Article : Google Scholar : PubMed/NCBI
41	Zhou XL, Wan L, Xu QR, Zhao Y and Liu JC: Notch signaling activation contributes to cardioprotection provided by ischemic preconditioning and postconditioning. J Transl Med. 11:2512013. View Article : Google Scholar : PubMed/NCBI
42	Zhou XL, Zhao Y, Fang YH, Xu QR and Liu JC: Hes1 is upregulated by ischemic postconditioning and contributes to cardioprotection. Cell Biochem Funct. 32:730–736. 2014. View Article : Google Scholar : PubMed/NCBI
43	Wang L, Lai S, Zou H, Zhou X, Wan Q, Luo Y, Wu Q, Wan L, Liu J and Huang H: Ischemic preconditioning/ischemic post-conditioning alleviates anoxia/reoxygenation injury via the Notch1/Hes1/VDAC1 axis. J Biochem Mol Toxicol. 36:e231992022. View Article : Google Scholar
44	Jiang X, Stockwell BR and Conrad M: Ferroptosis: Mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 22:266–282. 2021. View Article : Google Scholar : PubMed/NCBI
45	Wang X, Chen X, Zhou W, Men H, Bao T, Sun Y, Wang Q, Tan Y, Keller BB, Tong Q, et al: Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane via AMPK/NRF2 pathways. Acta Pharm Sin B. 12:708–722. 2022. View Article : Google Scholar : PubMed/NCBI
46	Galy B, Conrad M and Muckenthaler M: Mechanisms controlling cellular and systemic iron homeostasis. Nat Rev Mol Cell Biol. 25:133–155. 2024. View Article : Google Scholar
47	Jankowska EA, Kasztura M, Sokolski M, Bronisz M, Nawrocka S, Oleśkowska-Florek W, Zymliński R, Biegus J, Siwołowski P, Banasiak W, et al: Iron deficiency defined as depleted iron stores accompanied by unmet cellular iron requirements identifies patients at the highest risk of death after an episode of acute heart failure. Eur Heart J. 35:2468–2476. 2014. View Article : Google Scholar : PubMed/NCBI
48	Fang X, Cai Z, Wang H, Han D, Cheng Q, Zhang P, Gao F, Yu Y, Song Z, Wu Q, et al: Loss of cardiac ferritin H facilitates cardiomyopathy via Slc7a11-mediated ferroptosis. Circ Res. 127:486–501. 2020. View Article : Google Scholar : PubMed/NCBI
49	Fleming RE and Ponka P: Iron overload in human disease. N Engl J Med. 366:348–359. 2012. View Article : Google Scholar : PubMed/NCBI
50	Li D, Zhang G, Wang Z, Guo J, Liu Y, Lu Y, Qin Z, Xu Y, Cao C, Wang B, et al: Idebenone attenuates ferroptosis by inhibiting excessive autophagy via the ROS-AMPK-mTOR pathway to preserve cardiac function after myocardial infarction. Eur J Pharmacol. 943:1755692023. View Article : Google Scholar : PubMed/NCBI
51	Ye Y, Chen A, Li L, Liang Q, Wang S, Dong Q, Fu M, Lan Z, Li Y, Liu X, et al: Repression of the antiporter SLC7A11/glutathione/glutathione peroxidase 4 axis drives ferroptosis of vascular smooth muscle cells to facilitate vascular calcification. Kidney Int. 102:1259–1275. 2022. View Article : Google Scholar : PubMed/NCBI
52	Ikeda S, Zablocki D and Sadoshima J: The role of autophagy in death of cardiomyocytes. J Mol Cell Cardiol. 165:1–8. 2022. View Article : Google Scholar :
53	Liu W, Chen C, Gu X, Zhang L, Mao X, Chen Z and Tao L: AM1241 alleviates myocardial ischemia-reperfusion injury in rats by enhancing Pink1/Parkin-mediated autophagy. Life Sci. 272:1192282021. View Article : Google Scholar : PubMed/NCBI
54	Li Y, Liang P, Jiang B, Tang Y, Liu X, Liu M, Sun H, Chen C, Hao H, Liu Z, et al: CARD9 promotes autophagy in cardiomyocytes in myocardial ischemia/reperfusion injury via interacting with Rubicon directly. Basic Res Cardiol. 115:292020. View Article : Google Scholar : PubMed/NCBI
55	Wen L, Cheng X, Fan Q, Chen Z, Luo Z, Xu T, He M and He H: TanshinoneⅡA inhibits excessive autophagy and protects myocardium against ischemia/reperfusion injury via 14-3-3η/Akt/Beclin1 pathway. Eur J Pharmacol. 954:1758652023. View Article : Google Scholar
56	Fan G, Yu J, Asare PF, Wang L, Zhang H, Zhang B, Zhu Y and Gao X: Danshensu alleviates cardiac ischaemia/reperfusion injury by inhibiting autophagy and apoptosis via activation of mTOR signalling. J Cell Mol Med. 20:1908–1919. 2016. View Article : Google Scholar : PubMed/NCBI
57	Mohamed DZ, El-Sisi A, Sokar SS, Shebl AM and Abu-Risha SE: Targeting autophagy to modulate hepatic ischemia/reperfusion injury: A comparative study between octreotide and melatonin as autophagy modulators through AMPK/PI3K/AKT/mTOR/ULK1 and Keap1/Nrf2 signaling pathways in rats. Eur J Pharmacol. 897:1739202021. View Article : Google Scholar : PubMed/NCBI
58	Mancardi D, Pagliaro P, Ridnour LA, Tocchetti CG, Miranda K, Juhaszova M, Sollott SJ, Wink DA and Paolocci N: HNO protects the myocardium against reperfusion injury, inhibiting the mPTP opening via PKCε activation. Antioxidants (Basel). 11:3822022. View Article : Google Scholar
59	Pan P, Zhang H, Su L, Wang X and Liu D: Melatonin balance the autophagy and apoptosis by regulating UCP2 in the LPS-induced cardiomyopathy. Molecules. 23:6752018. View Article : Google Scholar : PubMed/NCBI