https://doi.org/10.4081/ejh.2024.4004
Resveratrol mediates mitochondrial function through the sirtuin 3 pathway to improve abnormal metabolic remodeling in atrial fibrillation
Submitted: 1 March 2024
Accepted: 9 April 2024
Published: 24 April 2024
Accepted: 9 April 2024
Abstract Views: 530
PDF: 185
HTML: 12
HTML: 12
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
This study investigated the impact of resveratrol on abnormal metabolic remodeling in atrial fibrillation (AF) and explored potential molecular mechanisms. An AF cell model was established by high-frequency electrical stimulation of HL-1 atrial muscle cells. Resveratrol concentrations were optimized using CCK-8 and flow cytometry. AF-induced increases in ROS and mitochondrial calcium, along with decreased adenosine triphosphate (ATP) and mitochondrial membrane potential, were observed. Resveratrol mitigated these changes and maintained normal mitochondrial morphology. Moreover, resveratrol acted through the SIRT3-dependent pathway, as evidenced by its ability to suppress AF-induced acetylation of key metabolic enzymes. SIRT3 overexpression controls acetylation modifications, suggesting its regulatory role. In conclusion, resveratrol's SIRT3-dependent pathway intervenes in AF-induced mitochondrial dysfunction, presenting a potential therapeutic avenue for AF-related metabolic disorders. This study sheds light on the role of resveratrol in mitigating AF-induced mitochondrial remodeling and highlights its potential as a novel treatment for AF.
Davidson KW, Barry MJ, Mangione CM, Cabana M, Caughey AB, Davis EM, et al. Screening for atrial fibrillation: US Preventive Services Task Force recommendation statement. JAMA 2022;327:360-7.
DOI: https://doi.org/10.1001/jama.2021.23732
Rahman F, Kwan GF, Benjamin EJ. Global epidemiology of atrial fibrillation. Nat Rev Cardiol 2014;11:639-54.
DOI: https://doi.org/10.1038/nrcardio.2014.118
Lippi G, Sanchis-Gomar F, Cervellin G. Global epidemiology of atrial fibrillation: An increasing epidemic and public health challenge. Int J Stroke 2021;16:217-21.
DOI: https://doi.org/10.1177/1747493019897870
Dan GA, Dobrev D. Antiarrhythmic drugs for atrial fibrillation: Imminent impulses are emerging. Ijc Heart Vasc 2018;21:11-5.
DOI: https://doi.org/10.1016/j.ijcha.2018.08.005
Wijesurendra RS, Casadei B. Mechanisms of atrial fibrillation. Heart 2019;105:1860-7.
DOI: https://doi.org/10.1136/heartjnl-2018-314267
Harada M, Melka J, Sobue Y, Nattel S. Metabolic considerations in atrial fibrillation - mechanistic insights and therapeutic opportunities. Circ J 2017;81:1749-57.
DOI: https://doi.org/10.1253/circj.CJ-17-1058
Jie QQ, Li G, Duan JB, Li XB, Yang W, Chu YP, et al. Remodeling of myocardial energy and metabolic homeostasis in a sheep model of persistent atrial fibrillation. Biochem Bioph Res Commun 2019;517:8-14.
DOI: https://doi.org/10.1016/j.bbrc.2019.05.112
Ozcan C, Li Z, Kim G, Jeevanandam V, Uriel N. Molecular mechanism of the association between atrial fibrillation and heart failure includes energy metabolic dysregulation due to mitochondrial dysfunction. J Card Fail 2019;25:911-20.
DOI: https://doi.org/10.1016/j.cardfail.2019.08.005
Tu T, Qin F, Bai F, Xiao Y, Ma Y, Li B, et al. Quantitative acetylated proteomics on left atrial appendage tissues revealed atrial energy metabolism and contraction status in patients with valvular heart disease with atrial fibrillation. Front Cardiovasc Med 2022;9:962036.
DOI: https://doi.org/10.3389/fcvm.2022.962036
Sarkaki A, Rashidi M, Ranjbaran M, Asareh ZDA, Shabaninejad Z, Behzad E, et al. Therapeutic effects of resveratrol on ischemia-reperfusion injury in the nervous system. Neurochem Res 2021;46:3085-102.
DOI: https://doi.org/10.1007/s11064-021-03412-z
Chong E, Chang SL, Hsiao YW, Singhal R, Liu SH, Leha T, et al. Resveratrol, a red wine antioxidant, reduces atrial fibrillation susceptibility in the failing heart by PI3K/AKT/eNOS signaling pathway activation. Heart Rhythm 2015;12:1046-56.
DOI: https://doi.org/10.1016/j.hrthm.2015.01.044
Baczko I, Light PE. Resveratrol and derivatives for the treatment of atrial fibrillation. Ann NY Acad Sci 2015;1348:68-74.
DOI: https://doi.org/10.1111/nyas.12843
Frommeyer G, Wolfes J, Ellermann C, Kochhauser S, Dechering DG, Eckardt L. Acute electrophysiologic effects of the polyphenols resveratrol and piceatannol in rabbit atria. Clin Exp Pharmacol P 2019;46:94-8.
DOI: https://doi.org/10.1111/1440-1681.13005
Arinno A, Apaijai N, Chattipakorn SC, Chattipakorn N. The roles of resveratrol on cardiac mitochondrial function in cardiac diseases. Eur J Nutr 2021;60:29-44.
DOI: https://doi.org/10.1007/s00394-020-02256-7
Zheng M, Bai Y, Sun X, Fu R, Liu L, Liu M, et al. Resveratrol reestablishes mitochondrial quality control in myocardial ischemia/reperfusion injury through Sirt1/Sirt3-Mfn2-Parkin-PGC-1α pathway. Molecules 2022;27:5545.
DOI: https://doi.org/10.3390/molecules27175545
Wang X, Huang Y, Zhang K, Chen F, Nie T, Zhao Y et al. Changes of energy metabolism in failing heart and its regulation by SIRT3. Heart Fail Rev 2023;28:977-992.
DOI: https://doi.org/10.1007/s10741-023-10295-5
Mao H, Zhang Y, Xiong Y, Zhu Z, Wang L, Liu X. Mitochondria-targeted antioxidant mitoquinone maintains mitochondrial homeostasis through the Sirt3-dependent pathway to mitigate oxidative damage caused by renal ischemia/reperfusion. Oxid Med Cell Longev 2022;2022:2213503.
DOI: https://doi.org/10.1155/2022/2213503
Mishra Y, Kaundal RK. Role of SIRT3 in mitochondrial biology and its therapeutic implications in neurodegenerative disorders. Drug Discov Today 2023;28:103583.
DOI: https://doi.org/10.1016/j.drudis.2023.103583
Yang J, Zhang Y, Pan Y, Sun C, Liu Z, Liu N, et al. The protective effect of 1,25(OH)(2)D(3) on myocardial function is mediated via sirtuin 3-regulated fatty acid metabolism. Front Cell Dev Biol 2021;9:627135.
DOI: https://doi.org/10.3389/fcell.2021.627135
Yu LM, Dong X, Xu YL, Zhou ZJ, Huang YT, Zhao JK, et al. Icariin attenuates excessive alcohol consumption-induced susceptibility to atrial fibrillation through SIRT3 signaling. Biochim Biophys Acta Mol Basis Dis 2022;1868:166483.
DOI: https://doi.org/10.1016/j.bbadis.2022.166483
Liu GZ, Xu W, Zang YX, Lou Q, Hang PZ, Gao Q, et al. Honokiol inhibits atrial metabolic remodeling in atrial fibrillation through Sirt3 pathway. Front Pharmacol 2022;13:813272.
Ko TH, Jeong D, Yu B, Song JE, Le QA, Woo SH, Choi JI. Inhibition of late sodium current via PI3K/Akt signaling prevents cellular remodeling in tachypacing-induced HL-1 atrial myocytes. Pflugers Arch 2023;475:217-231.
DOI: https://doi.org/10.1007/s00424-022-02754-z
Wiersma M, van Marion DMS, Wüst RCI, Houtkooper RH, Zhang D, Groot NMS, et al. Mitochondrial dysfunction underlies cardiomyocyte remodeling in experimental and clinical atrial fibrillation. Cells 2019;8:1202.
DOI: https://doi.org/10.3390/cells8101202
Pool L, Wijdeveld LFJM, de Groot NMS, Brundel BJJM. The role of mitochondrial dysfunction in atrial fibrillation: translation to druggable target and biomarker discovery. Int J Mol Sci 2021;22:8463.
DOI: https://doi.org/10.3390/ijms22168463
Stephan LS, Almeida ED, Markoski MM, Garavaglia J, Marcadenti A. Red wine, resveratrol and atrial fibrillation. Nutrients 2017;9:1190.
DOI: https://doi.org/10.3390/nu9111190
Yang S, Xu W, Dong Z, Zhou M, Lin C, Jin H, et al. TPEN prevents rapid pacing-induced calcium overload and nitration stress in HL-1 myocytes. Cardiovasc Ther 2015;33:200-8.
DOI: https://doi.org/10.1111/1755-5922.12134
Emelyanova L, Ashary Z, Cosic M, Negmadjanov U, Ross G, Rizvi F, et al. Selective downregulation of mitochondrial electron transport chain activity and increased oxidative stress in human atrial fibrillation. Am J Physiol Heart Circ Physiol 2016;311:H54-63.
DOI: https://doi.org/10.1152/ajpheart.00699.2015
Murphy E, Ardehali H, Balaban RS, DiLisa F, Dorn GN, Kitsis RN, et al. Mitochondrial function, biology, and role in disease: a scientific statement from the American Heart Association. Circ Res 2016;118:1960-91.
DOI: https://doi.org/10.1161/RES.0000000000000104
Bukowska A, Schild L, Keilhoff G, Hirte D, Neumann M, Gardemann A, et al. Mitochondrial dysfunction and redox signaling in atrial tachyarrhythmia. Exp Biol Med 2008;233:558-74.
DOI: https://doi.org/10.3181/0706-RM-155
Xie W, Santulli G, Reiken SR, Yuan Q, Osborne BW, Chen BX et al. Mitochondrial oxidative stress promotes atrial fibrillation. Sci Rep-Uk 2015;5:11427.
DOI: https://doi.org/10.1038/srep11427
Tu T, Zhou S, Liu Z, Li X, Liu Q. Quantitative proteomics of changes in energy metabolism-related proteins in atrial tissue from valvular disease patients with permanent atrial fibrillation. Circ J 2014;78:993-1001.
DOI: https://doi.org/10.1253/circj.CJ-13-1365
Mason FE, Pronto J, Alhussini K, Maack C, Voigt N. Cellular and mitochondrial mechanisms of atrial fibrillation. Basic Res Cardiol 2020;115:72.
DOI: https://doi.org/10.1007/s00395-020-00827-7
Eisner V, Picard M, Hajnoczky G. Mitochondrial dynamics in adaptive and maladaptive cellular stress responses. Nat Cell Biol 2018;20:755-65.
DOI: https://doi.org/10.1038/s41556-018-0133-0
Tong Z, Xie Y, He M, Ma W, Zhou Y, Lai S, et al. VDAC1 deacetylation is involved in the protective effects of resveratrol against mitochondria-mediated apoptosis in cardiomyocytes subjected to anoxia/reoxygenation injury. Biomed Pharmacother 2017;95:77-83.
DOI: https://doi.org/10.1016/j.biopha.2017.08.046
Jeong SH, Hanh TM, Kim HK, Lee SR, Song IS, Noh SJ, et al. HS-1793, a recently developed resveratrol analogue protects rat heart against hypoxia/reoxygenation injury via attenuating mitochondrial damage. Bioorg Med Chem Lett 2013;23:4225-9.
DOI: https://doi.org/10.1016/j.bmcl.2013.05.010
Wang R, Xu H, Tan B, Yi Q, Sun Y, Xiang H, et al. SIRT3 promotes metabolic maturation of human iPSC-derived cardiomyocytes via OPA1-controlled mitochondrial dynamics. Free Radical Biol Med 2023;195:270-82.
DOI: https://doi.org/10.1016/j.freeradbiomed.2022.12.101
Tu T, Zhou S, Liu Q. Acetylation: a potential "regulating valve" of cardiac energy metabolism during atrial fibrillation. Int J Cardiol 2014;177:71-2.
DOI: https://doi.org/10.1016/j.ijcard.2014.09.022
Afzaal A, Rehman K, Kamal S, Akash M. Versatile role of sirtuins in metabolic disorders: From modulation of mitochondrial function to therapeutic interventions. J Biochem Mol Toxic 2022;36:e23047.
DOI: https://doi.org/10.1002/jbt.23047
Liu GZ, Xu W, Zang YX, Lou Q, Hang PZ, Gao Q, et al. Honokiol inhibits atrial metabolic remodeling in atrial fibrillation through Sirt3 pathway. Front Pharmacol 2022;13:813272.
DOI: https://doi.org/10.3389/fphar.2022.813272
Supporting Agencies
This work was supported by the Tianjin Medical Key Discipline (Specialty) Construction ProjectHow to Cite
Cao, Y., Cui, L., Tuo, S., Liu, H., & Cui, S. (2024). Resveratrol mediates mitochondrial function through the sirtuin 3 pathway to improve abnormal metabolic remodeling in atrial fibrillation. European Journal of Histochemistry, 68(2). https://doi.org/10.4081/ejh.2024.4004
Copyright (c) 2024 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.
