Delayed reperfusion of the ischemic heart (I/R) is known to impair the recovery of cardiac function and produce a wide variety of myocardial defects, including ultrastructural damage, metabolic alterations, subcellular Ca2+-handling abnormalities, activation of proteases, and changes in cardiac gene expression. Although I/R injury has been reported to induce the formation of reactive oxygen species (ROS), inflammation, and intracellular Ca2+ overload, the generation of oxidative stress is considered to play a critical role in the development of cardiac dysfunction. Increases in the production of superoxide, hydroxyl radicals, and oxidants, such as hydrogen peroxide and hypochlorous acid, occur in hearts subjected to I/R injury. In fact, mitochondria are a major source of the excessive production of ROS in I/R hearts due to impairment in the electron transport system as well as activation of xanthine oxidase and NADPH oxidase. Nitric oxide synthase, mainly present in the endothelium, is also activated due to I/R injury, leading to the production of nitric oxide, which, upon combination with superoxide radicals, generates nitrosative stress. Alterations in cardiac function, sarcolemma, sarcoplasmic reticulum Ca2+-handling activities, mitochondrial oxidative phosphorylation, and protease activation due to I/R injury are simulated upon exposing the heart to the oxyradical-generating system (xanthine plus xanthine oxidase) or H2O2. On the other hand, the activation of endogenous antioxidants such as superoxide dismutase, catalase, glutathione peroxidase, and the concentration of a transcription factor (Nrf2), which modulates the expression of various endogenous antioxidants, is depressed due to I/R injury in hearts. Furthermore, pretreatment of hearts with antioxidants such as catalase plus superoxide dismutase, N-acetylcysteine, and mercaptopropionylglycerine has been observed to attenuate I/R-induced subcellular Ca2+ handling and changes in Ca2+-regulatory activities; additionally, it has been found to depress protease activation and improve the recovery of cardiac function. These observations indicate that oxidative stress is intimately involved in the pathological effects of I/R injury and different antioxidants attenuate I/R-induced subcellular alterations and improve the recovery of cardiac function. Thus, we are faced with the task of developing safe and effective antioxidants as well as agents for upregulating the expression of endogenous antioxidants for the therapy of I/R injury.

Asper Clinical Research Institute St Boniface Hospital Winnipeg MB R2H 2A6 Canada

Department of Cardiology 2nd Faculty of Medicine Charles University Motol University Hospital 5 Uvalu 84 15000 Prague Czech Republic

St Boniface Hospital Albrechtsen Research Centre Institute of Cardiovascular Sciences Department of Physiology and Pathophysiology Max Rady College of Medicine University of Manitoba Winnipeg MB R2H 2A6 Canada

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Sharma G.P., Varley K.G., Kim S.W., Barwinsky J., Cohen M., Dhalla N.S. Alterations in energy metabolism and ultrastructure upon reperfusion of the ischemic myocardium after coronary occlusion. Am. J. Cardiol. 1975;36:234–243. doi: 10.1016/0002-9149(75)90532-9. PubMed DOI

Nayler W.G., Panagiotopoulos S., Elz J.S., Daly M.J. Calcium-mediated damage during post-ischemic reperfusion. J. Mol. Cell. Cardiol. 1988;20((Suppl. S2)):41–54. doi: 10.1016/0022-2828(88)90331-8. PubMed DOI

Murphy J.G., Smith T.W., Marsh J.D. Mechanisms of reoxygenation-induced calcium overload in cultured chick embryo heart cells. Am. J. Physiol. 1988;254:H1133–H1141. doi: 10.1152/ajpheart.1988.254.6.H1133. PubMed DOI

Jennings R.B., Reimer K.A. The cell biology of acute myocardial ischemia. Annu. Rev. Med. 1991;42:225–246. doi: 10.1146/annurev.me.42.020191.001301. PubMed DOI

Bolli R., Marban E. Molecular and cellular mechanisms of myocardial stunning. Physiol. Rev. 1999;79:609–634. doi: 10.1152/physrev.1999.79.2.609. PubMed DOI

Piper M.H., Meuter K., Schafer C. Cellular mechanisms of ischemia-reperfusion injury. Ann. Thorac. Surg. 2003;75:S644–S648. doi: 10.1016/S0003-4975(02)04686-6. PubMed DOI

Hoffman J.W., Gilbert T.B., Poston R.S., Silldorff E.P. Myocardial reperfusion injury: Etiology, mechanisms, and therapies. J. ExtraCorporeal Technol. 2004;36:391–411. doi: 10.1051/ject/2004364391. PubMed DOI

Dhalla N.S., Elmoselhi A.B., Hata T., Makino N. Status of myocardial antioxidants in ischemia-reperfusion injury. Cardiovasc. Res. 2000;47:446–456. doi: 10.1016/S0008-6363(00)00078-X. PubMed DOI

Neuzil J., Rayner B.S., Lowe H.C., Witting P.K. Oxidative stress in myocardial ischemia reperfusion injury: A renewed focus on a long-standing area of heart research. Redox Rep. 2005;10:187–197. doi: 10.1179/135100005X57391. PubMed DOI

Milei J., Grana D.R., Forcada P., Ambrosio G. Mitochondrial oxidative and structural damage in ischemia-reperfusion in human myocardium. Current knowledge and future directions. Front. Biosci. 2007;12:1124–1130. doi: 10.2741/2131. PubMed DOI

Dhalla N.S., Saini H.K., Tappia P.S., Sethi R., Mengi S.A., Gupta S.K. Potential role and mechanisms of subcellular remodeling in cardiac dysfunction due to ischemic heart disease. J. Cardiovasc. Med. 2007;8:238–250. doi: 10.2459/01.JCM.0000263489.13479.68. PubMed DOI

Rodrigo R., Libuy M., Feliu F., Hasson D. Oxidative stress-related biomarkers in essential hypertension and ischemia-reperfusion myocardial damage. Dis. Markers. 2013;35:773–790. doi: 10.1155/2013/974358. PubMed DOI PMC

Neri M., Riezzo I., Pascale N., Pomara C., Turillazzi E. Ischemia/reperfusion injury following acute myocardial infarction: A critical issue for clinicians and forensic pathologists. Mediat. Inflamm. 2017;2017:7018393. doi: 10.1155/2017/7018393. PubMed DOI PMC

Zhou T., Chuang C.C., Zuo L. Molecular characterization of reactive oxygen species in myocardial ischemia-reperfusion injury. BioMed Res. Int. 2015;2015:864946. doi: 10.1155/2015/864946. PubMed DOI PMC

Kurian G.A., Rajagopal R., Vedantham S., Rajesh M. The role of oxidative stress in myocardial ischemia and reperfusion injury and remodeling: Revisited. Oxidative Med. Cell. Longev. 2016;2016:165450. doi: 10.1155/2016/1656450. PubMed DOI PMC

Morciano G., Pinton P. Modulation of mitochondrial permeability transition pores in reperfusion injury: Mechanisms and therapeutic approaches. Eur. J. Clin. Investig. 2025;55:e14331. doi: 10.1111/eci.14331. PubMed DOI PMC

Liu Y., Wu H., Zhou G., Zhang D., Yang Q., Li Y., Yang X., Sun J. Role of M6a Methylation in Myocardial Ischemia-Reperfusion Injury and Doxorubicin-Induced Cardiotoxicity. Cardiovasc. Toxicol. 2024;24:918–928. doi: 10.1007/s12012-024-09898-7. PubMed DOI

Li J., Zhang Y., Tang R., Liu H., Li X., Lei W., Chen J., Jin Z., Tang J., Wang Z., et al. Glycogen synthase kinase-3β: A multifaceted player in ischemia-reperfusion injury and its therapeutic prospects. J. Cell Physiol. 2024;239:e31335. doi: 10.1002/jcp.31335. PubMed DOI

Balderas E., Lee S.H.J., Rai N.K., Mollinedo D.M., Duron H.E., Chaudhuri D. Mitochondrial calcium regulation of cardiac metabolism in health and disease. Physiology. 2024;39:247–268. doi: 10.1152/physiol.00014.2024. PubMed DOI PMC

Nakamura E., Aoki T., Endo Y., Kazmi J., Hagiwara J., Kuschner C.E., Yin T., Kim J., Becker L.B., Hayashida K. Organ-specific mitochondrial alterations following ischemia-reperfusion injury in post-cardiac arrest syndrome: A comprehensive review. Life. 2024;14:477. doi: 10.3390/life14040477. PubMed DOI PMC

Yan Z., Xing Z., Xue T., Zhao J., Li G., Xu L., Sun Q. Insulin-like growth factor-1 in myocardial ischemia-reperfusion injury: A review. Medicine. 2024;103:e37279. doi: 10.1097/MD.0000000000037279. PubMed DOI PMC

Wang Y., Xu R., Yan Y., He B., Miao C., Fang Y., Wan H., Zhou G. Exosomes-mediated signaling pathway: A new direction for treatment of organ ischemia-reperfusion injury. Biomedicines. 2024;12:353. doi: 10.3390/biomedicines12020353. PubMed DOI PMC

Liao W., Wen Y., Yang S., Duan Y., Liu Z. Research progress and perspectives of N-methyl-D-aspartate receptor in myocardial and cerebral ischemia-reperfusion injury: A review. Medicine. 2023;102:e35490. doi: 10.1097/MD.0000000000035490. PubMed DOI PMC

Omorou M., Huang Y., Gao M., Mu C., Xu W., Han Y., Xu H. The forkhead box O3 (FOXO3): A key player in the regulation of ischemia and reperfusion injury. Cell. Mol. Life Sci. 2023;80:102. doi: 10.1007/s00018-023-04755-2. PubMed DOI PMC

Galeone A., Grano M., Brunetti G. Tumor necrosis factor family members and myocardial ischemia-reperfusion injury: State of the art and therapeutic implications. Int. J. Mol. Sci. 2023;24:4606. doi: 10.3390/ijms24054606. PubMed DOI PMC

Popov S.V., Mukhomedzyanov A.V., Voronkov N.S., Derkachev I.A., Boshchenko A.A., Fu F., Sufianova G.Z., Khlestkina M.S., Maslov L.N. Regulation of autophagy of the heart in ischemia and reperfusion. Apoptosis. 2023;28:55–80. doi: 10.1007/s10495-022-01786-1. PubMed DOI

Mahdiani S., Omidkhoda N., Rezaee R., Heidari S., Karimi G. Induction of JAK2/STAT3 pathway contributes to protective effects of different therapeutics against myocardial ischemia/reperfusion. Biomed. Pharmacother. 2022;155:113751. doi: 10.1016/j.biopha.2022.113751. PubMed DOI

Bai Y., Wu J., Yang Z., Wang X., Zhang D., Ma J. Mitochondrial quality control in cardiac ischemia/reperfusion injury: New insights into mechanisms and implications. Cell Biol. Toxicol. 2023;39:33–51. doi: 10.1007/s10565-022-09716-2. PubMed DOI

Liu H., Liu X., Zhou J., Li T. Mitochondrial DNA is a vital driving force in ischemia-reperfusion injury in cardiovascular diseases. Oxidative Med. Cell. Longev. 2022;2022:6235747. doi: 10.1155/2022/6235747. PubMed DOI PMC

He J., Liu D., Zhao L., Zhou D., Rong J., Zhang L., Xia Z. Myocardial ischemia/reperfusion injury: Mechanisms of injury and implications for management. Exp. Ther. Med. 2022;23:430. doi: 10.3892/etm.2022.11357. PubMed DOI PMC

Maslov L.N., Popov S.V., Mukhomedzyanov A.V., Naryzhnaya N.V., Voronkov N.S., Ryabov V.V., Boshchenko A.A., Khaliulin I., Prasad N.R., Fu F., et al. Reperfusion cardiac injury: Receptors and the signaling mechanisms. Curr. Cardiol. Rev. 2022;18:63–79. doi: 10.2174/1573403X18666220413121730. PubMed DOI PMC

Zhuang Y., Yu M.L., Lu S.F. Purinergic signaling in myocardial ischemia-reperfusion injury. Purinergic Signal. 2023;19:229–243. doi: 10.1007/s11302-022-09856-4. PubMed DOI PMC

Casin K.M., Calvert J.W. Dynamic regulation of cysteine oxidation and phosphorylation in myocardial ischemia-reperfusion injury. Cells. 2021;10:2388. doi: 10.3390/cells10092388. PubMed DOI PMC

Chen L., Shi D., Guo M. The roles of PKC-δ and PKC-ε in myocardial ischemia/reperfusion injury. Pharmacol. Res. 2021;170:105716. doi: 10.1016/j.phrs.2021.105716. PubMed DOI

Zheng J., Chen P., Zhong J., Cheng Y., Chen H., He Y., Chen C. HIF-1α in myocardial ischemia-reperfusion injury. Mol. Med. Rep. 2021;23:352. doi: 10.3892/mmr.2021.11991. PubMed DOI PMC

Jin S., Kang P.M. A systematic review on advances in management of oxidative stress-associated cardiovascular diseases. Antioxidants. 2024;13:923. doi: 10.3390/antiox13080923. PubMed DOI PMC

Chen X., Yang Y., Zhou Z., Yu H., Zhang S., Huang S., Wei Z., Ren K., Jin Y. Unraveling the complex interplay between Mitochondria-Associated Membranes (MAMs) and cardiovascular inflammation: Molecular mechanisms and therapeutic implications. Int. Immunopharmacol. 2024;141:112930. doi: 10.1016/j.intimp.2024.112930. PubMed DOI

Zhang J., Zhao Y., Gong N. Endoplasmic reticulum stress signaling modulates ischemia/reperfusion injury in the aged heart by regulating mitochondrial maintenance. Mol. Med. 2024;30:107. doi: 10.1186/s10020-024-00869-w. PubMed DOI PMC

Zhang H., Dhalla N.S. The role of pro-inflammatory cytokines in the pathogenesis of cardiovascular disease. Int. J. Mol. Sci. 2024;25:1082. doi: 10.3390/ijms25021082. PubMed DOI PMC

Ruan Y., Zeng J., Jin Q., Chu M., Ji K., Wang Z., Li L. Endoplasmic reticulum stress serves an important role in cardiac ischemia/reperfusion injury. Exp. Ther. Med. 2020;20:268. doi: 10.3892/etm.2020.9398. PubMed DOI PMC

Shah A.K., Bhullar S.K., Elimban V., Dhalla N.S. Oxidative stress as a mechanism for functional alterations in cadiac hypertrophy and heart failure. Antioxidants. 2021;10:931. doi: 10.3390/antiox10060931. PubMed DOI PMC

Dhalla N.S., Elimban V., Shah A.K., Nusier M. Mechanisms of cardiac dysfunction in heart failure due to myocardial infarction. J. Integr. Cardiol. 2019;2:3–7. doi: 10.31487/j.JICOA.2019.04.12. DOI

Dhalla N.S., Temsah R.M., Netticadan T. Role of oxidative stress in cardiovascular diseases. J. Hypertens. 2000;18:655–673. doi: 10.1097/00004872-200018060-00002. PubMed DOI

Dhalla N.S., Elimban V., Bartekova M., Adameova A. Involvement of oxidative stress in the development of subcellular defects and heart disease. Biomedicines. 2022;10:393. doi: 10.3390/biomedicines10020393. PubMed DOI PMC

Saini H.K., Xu Y.J., Zhang M., Liu P.P., Kirshenbaum L.A., Dhalla N.S. Role of tumor necrosis factor-alpha and other cytokines in ischemia-reperfusion-induced injury in the heart. Exp. Clin. Cardiol. 2005;10:213–222. PubMed PMC

Ambrosio G., Zweier J.L., Flaherty J.T. The relationship between oxygen radical generation and impairment of myocardial energy metabolism following post-ischemic reperfusion. J. Mol. Cell. Cardiol. 1991;23:1359–1374. doi: 10.1016/0022-2828(91)90183-M. PubMed DOI

Sinning C., Westermann D., Clemmensen P. Oxidative stress in ischemia and reperfusion: Current concepts, novel ideas and future perspectives. Biomark. Med. 2017;11:11031–11040. doi: 10.2217/bmm-2017-0110. PubMed DOI

Bartekova M., Barancik M., Ferenczyova K., Dhalla N.S. Beneficial effects of N-acetylcysteine and N–N-mercaptopropionylglycine on Ischemia reperfusion injury in the heart. Curr. Med. Chem. 2018;25:355–366. doi: 10.2174/0929867324666170608111917. PubMed DOI

Ferrari R., Ceconi C., Curello S., Guarnieri C., Caldarera C.M., Albertini A., Visioli O. Oxygen-mediated myocardial damage during ischemia and reperfusion: Role of the cellular defenses against oxygen toxicity. J. Mol. Cell. Cardiol. 1985;17:937–945. doi: 10.1016/S0022-2828(85)80074-2. PubMed DOI

Arduini A., Mezzetti A., Porreca E., Lapenna D., DeJulia J., Marzio L., Polidoro G., Cuccurullo F. Effect of ischemia and reperfusion on antioxidant enzymes and mitochondrial inner membrane proteins in perfused rat heart. Biochim. Biophys. Acta. 1988;970:113–121. doi: 10.1016/0167-4889(88)90169-3. PubMed DOI

Dhalla N.S., Shah A.K., Adameova A., Bartekova M. Role of oxidative stress in cardiac dysfunction and subcellular defects due to ischemia-reperfusion injury. Biomedicines. 2022;10:1473. doi: 10.3390/biomedicines10071473. PubMed DOI PMC

San-Martín-Martínez D., Serrano-Lemus D., Cornejo V., Gajardo A.I.J., Rodrigo R. Pharmacological basis for abrogating myocardial reperfusion injury through a multi-target combined antioxidant therapy. Clin. Pharmacokinet. 2022;61:1203–1218. doi: 10.1007/s40262-022-01151-0. PubMed DOI

Matsushima S., Sadoshima J. Yin and Yang of NADPH oxidases in myocardial ischemia-reperfusion. Antioxidants. 2022;11:1069. doi: 10.3390/antiox11061069. PubMed DOI PMC

Chen C.L., Zhang L., Jin Z., Kasumov T., Chen Y.R. Mitochondrial redox regulation and myocardial ischemia-reperfusion injury. Am. J. Physiol. Cell Physiol. 2022;322:C12–C23. doi: 10.1152/ajpcell.00131.2021. PubMed DOI PMC

Wang M., Liu Y., Liang Y., Naruse K., Takahashi K. Systematic understanding of pathophysiological mechanisms of oxidative stress-related conditions-diabetes mellitus, cardiovascular diseases, and ischemia-reperfusion injury. Front. Cardiovasc. Med. 2021;8:649785. doi: 10.3389/fcvm.2021.649785. PubMed DOI PMC

Hu L., Wang Z., Carmone C., Keijer J., Zhang D. Role of oxidative DNA damage and repair in atrial fibrillation and ischemic heart disease. Int. J. Mol. Sci. 2021;22:3838. doi: 10.3390/ijms22083838. PubMed DOI PMC

Dambrova M., Zuurbier C.J., Borutaite V., Liepinsh E., Makrecka-Kuka M. Energy substrate metabolism and mitochondrial oxidative stress in cardiac ischemia/reperfusion injury. Free Radic. Biol. Med. 2021;165:24–37. doi: 10.1016/j.freeradbiomed.2021.01.036. PubMed DOI

Huang P., Qu C., Rao Z., Wu D., Zhao J. Bidirectional regulation mechanism of TRPM2 channel: Role in oxidative stress, inflammation and ischemia-reperfusion injury. Front. Immunol. 2024;15:1391355. doi: 10.3389/fimmu.2024.1391355. PubMed DOI PMC

Liang W.L., Cai M.R., Zhang M.Q., Cui S., Zhang T.R., Cheng W.H., Wu Y.H., Ou W.J., Jia Z.H., Zhang S.F. Chinese herbal medicine alleviates myocardial ischemia/reperfusion injury by regulating endoplasmic reticulum stress. Evid. Based Complement. Altern. Med. 2021;2021:4963346. doi: 10.1155/2021/4963346. PubMed DOI PMC

Wiklund L., Sharma A., Patnaik R., Muresanu D.F., Sahib S., Tian Z.R., Castellani R.J., Nozari A., Lafuente J.V., Sharma H.S. Upregulation of hemeoxygenase enzymes HO-1 and HO-2 following ischemia-reperfusion injury in connection with experimental cardiac arrest and cardiopulmonary resuscitation: Neuroprotective effects of methylene blue. Prog. Brain Res. 2021;265:317–375. PubMed

Thompson J., Maceyka M., Chen Q. Targeting ER stress and calpain activation to reverse age-dependent mitochondrial damage in the heart. Mech. Ageing Dev. 2020;192:111380. doi: 10.1016/j.mad.2020.111380. PubMed DOI PMC

Dubois-Deruy E., Peugnet V., Turkieh A., Pinet F. Oxidative stress in cardiovascular diseases. Antioxidants. 2020;9:864. doi: 10.3390/antiox9090864. PubMed DOI PMC

Zhao S., Cheng C.K., Zhang C.L., Huang Y. Interplay between oxidative stress, cyclooxygenases, and prostanoids in cardiovascular diseases. Antioxid. Redox Signal. 2021;34:784–799. doi: 10.1089/ars.2020.8105. PubMed DOI

Bugger H., Pfeil K. Mitochondrial ROS in myocardial ischemia reperfusion and remodeling. Biochim. Biophys. Acta Mol. Basis Dis. 2020;1866:165768. doi: 10.1016/j.bbadis.2020.165768. PubMed DOI

Zhou H., Toan S. Pathological roles of mitochondrial oxidative stress and mitochondrial dynamics in cardiac microvascular ischemia/reperfusion injury. Biomolecules. 2020;10:85. doi: 10.3390/biom10010085. PubMed DOI PMC

Zhang Y., Murugesan P., Huang K., Cai H. NADPH oxidases and oxidase crosstalk in cardiovascular diseases: Novel therapeutic targets. Nat. Rev. Cardiol. 2020;17:170–194. doi: 10.1038/s41569-019-0260-8. PubMed DOI PMC

Fibbi B., Marroncini G., Naldi L., Peri A. The Yin and Yang effect of the apelinergic system in oxidative stress. Int. J. Mol. Sci. 2023;24:4745. doi: 10.3390/ijms24054745. PubMed DOI PMC

Qiu M., Chen J., Li X., Zhuang J. Intersection of the ubiquitin-proteasome system with oxidative stress in cardiovascular disease. Int. J. Mol. Sci. 2022;23:12197. doi: 10.3390/ijms232012197. PubMed DOI PMC

Szyller J., Jagielski D., Bil-Lula I. Antioxidants in arrhythmia treatment-still a controversy? A review of selected clinical and laboratory research. Antioxidants. 2022;11:1109. doi: 10.3390/antiox11061109. PubMed DOI PMC

Adameova A., Shah A.K., Dhalla N.S. Role of oxidative stress in the genesis of ventricular arrhythmias. Int. J. Mol. Sci. 2020;21:4200. doi: 10.3390/ijms21124200. PubMed DOI PMC

Luan X., Chen P., Miao L., Yuan X., Yu C., Di G. Ferroptosis in organ ischemia-reperfusion injuries: Recent advancements and strategies. Mol. Cell. Biochem. 2025;480:19–41. doi: 10.1007/s11010-024-04978-2. PubMed DOI

Wang R., Chen X., Li X., Wang K. Molecular therapy of cardiac ischemia-reperfusion injury based on mitochondria and ferroptosis. J. Mol. Med. 2023;101:1059–1071. doi: 10.1007/s00109-023-02346-z. PubMed DOI

Fratta Pasini A.M., Stranieri C., Busti F., Di Leo E.G., Girelli D., Cominacini L. New insights into the role of ferroptosis in cardiovascular diseases. Cells. 2023;12:867. doi: 10.3390/cells12060867. PubMed DOI PMC

Yu Y., Yan Y., Niu F., Wang Y., Chen X., Su G., Liu Y., Zhao X., Qian L., Liu P., et al. Ferroptosis: A cell death connecting oxidative stress, inflammation and cardiovascular diseases. Cell Death Discov. 2021;7:193. doi: 10.1038/s41420-021-00579-w. PubMed DOI PMC

Lillo-Moya J., Rojas-Solé C., Muñoz-Salamanca D., Panieri E., Saso L., Rodrigo R. Targeting ferroptosis against ischemia/reperfusion cardiac injury. Antioxidants. 2021;10:667. doi: 10.3390/antiox10050667. PubMed DOI PMC

Tian K., Yang Y., Zhou K., Deng N., Tian Z., Wu Z., Liu X., Zhang F., Jiang Z. The role of ROS-induced pyroptosis in CVD. Front. Cardiovasc. Med. 2023;10:1116509. doi: 10.3389/fcvm.2023.1116509. PubMed DOI PMC

Liu Y., Zhang J., Zhang D., Yu P., Zhang J., Yu S. Research progress on the role of pyroptosis in myocardial ischemia-reperfusion injury. Cells. 2022;11:3271. doi: 10.3390/cells11203271. PubMed DOI PMC

Adameova A., Horvath C., Abdul-Ghani S., Varga Z.V., Suleiman M.S., Dhalla N.S. Interplay of oxidative stress and necrosis-like cell death in cardiac ischemia/reperfusion injury: A focus on necroptosis. Biomedicines. 2022;10:127. doi: 10.3390/biomedicines10010127. PubMed DOI PMC

Cinato M., Andersson L., Miljanovic A., Laudette M., Kunduzova O., Borén J., Levin M.C. Role of perilipins in oxidative stress-implications for cardiovascular disease. Antioxidants. 2024;13:209. doi: 10.3390/antiox13020209. PubMed DOI PMC

Rongjin H., Feng C., Jun K., Shirong L. Oxidative stress-induced protein of SESTRIN2 in cardioprotection effect. Dis. Markers. 2022;2022:7439878. doi: 10.1155/2022/7439878. PubMed DOI PMC

Cai H., Liu Y., Men H., Zheng Y. Protective mechanism of humanin against oxidative stress in aging-related cardiovascular diseases. Front. Endocrinol. 2021;12:683151. doi: 10.3389/fendo.2021.683151. PubMed DOI PMC

Liu Y., Wang M., Liang Y., Wang C., Naruse K., Takahashi K. Treatment of oxidative stress with exosomes in myocardial ischemia. Int. J. Mol. Sci. 2021;22:1729. doi: 10.3390/ijms22041729. PubMed DOI PMC

Wang W., Kang P.M. Oxidative stress and antioxidant treatments in cardiovascular diseases. Antioxidants. 2020;9:1292. doi: 10.3390/antiox9121292. PubMed DOI PMC

Wu W., Lai L., Xie M., Qiu H. Insights of heat shock protein 22 in the cardiac protection against ischemic oxidative stress. Redox Biol. 2020;34:101555. doi: 10.1016/j.redox.2020.101555. PubMed DOI PMC

Kura B., Szeiffova Bacova B., Kalocayova B., Sykora M., Slezak J. Oxidative stress-responsive microRNAs in heart injury. Int. J. Mol. Sci. 2020;21:358. doi: 10.3390/ijms21010358. PubMed DOI PMC

Haramaki N., Stewart D.B., Aggarwal S., Ikeda H., Reznick A.Z., Packer L. Networking antioxidants in the isolated rat heart are selectively depleted by ischemia-reperfusion. Free Radic. Biol. Med. 1998;25:329–339. doi: 10.1016/S0891-5849(98)00066-5. PubMed DOI

Dhalla N.S., Golfman L., Takeda S., Takeda N., Nagano M. Evidence for the role of oxidative stress in acute ischemic heart disease: A brief review. Can. J. Cardiol. 1999;15:587–593. PubMed

Saini H.K., Machackova J., Dhalla N.S. Role of reactive oxygen species in ischemic preconditioning of subcellular organelles in the heart. Antioxid. Redox Signal. 2004;6:393–404. doi: 10.1089/152308604322899468. PubMed DOI

Bhullar S.K., Shah A.K., Dhalla N.S. Role of angiotensin II in the development of subcellular remodeling in heart failure. Explor. Med. 2021;2:352–371. doi: 10.37349/emed.2021.00054. DOI

Tappia P.S., Shah A.K., Ramjiawan B., Dhalla N.S. Modification of ischemia/reperfusion-induced alterations in subcellular organelles by ischemic preconditioning. Int. J. Mol. Sci. 2022;23:3425. doi: 10.3390/ijms23073425. PubMed DOI PMC

Bhosale G., Sharpe J.A., Sundier S., Duchen M. Calcium signaling as mediator of cell energy demand and a trigger to cell death. Ann. N. Y. Acad. Sci. 2015;1350:107–116. doi: 10.1111/nyas.12885. PubMed DOI PMC

Badalzadeh R., Mokhtari B., Yavari R. Contribution of apoptosis in myocardial reperfusion injury and loss of cardioprotection in diabetes mellitus. J. Physiol. Sci. 2015;65:201–215. doi: 10.1007/s12576-015-0365-8. PubMed DOI PMC

Ferrari R., Guardigli G., Mele D., Percoco G.F., Ceconi C., Curello S. Oxidative stress during myocardial ischemia and heart failure. Curr. Pharm. Des. 2004;10:1699–1711. doi: 10.2174/1381612043384718. PubMed DOI

Neri M., Fineschi V., Di Paolo M., Pomara C., Riezzo I., Turillazzi E., Cerretani D. Cardiac oxidative stress and inflammation cytokines response after myocardial infarction. Curr. Vasc. Pharmacol. 2015;13:26–36. doi: 10.2174/15701611113119990003. PubMed DOI

Li X., Zhang F., Zhou H., Hu Y., Guo D., Fang X., Chen Y. Interplay of TNF-α, soluble TNF receptors and oxidative stress in coronary chronic total occlusion of the oldest patients with coronary heart disease. Cytokine. 2020;125:154836. doi: 10.1016/j.cyto.2019.154836. PubMed DOI

Xiong W., Qu Y., Chen H., Qian J. Insight into long noncoding RNA-miRNA-mRNA axes in myocardial ischemia-reperfusion injury: The implications for mechanism and therapy. Epigenomics. 2019;11:1733–1748. doi: 10.2217/epi-2019-0119. PubMed DOI

Zhao Z., Sun W., Guo Z., Liu B., Yu H., Zhang J. Long noncoding RNAs in myocardial ischemia-reperfusion inury. Oxidative Med. Cell. Longev. 2021;2021:8889123. doi: 10.1155/2021/8889123. PubMed DOI PMC

Li Q., Li Z., Fan Z., Yang Y., Lu C. Involvement of non-coding RNAs in the pathogenesis of myocardial ischemia/reperfusion injury. Int. J. Mol. Med. 2021;47:42. doi: 10.3892/ijmm.2021.4875. PubMed DOI PMC

Wang B.F., Yoshioka J. The emerging role of thioredoxin-interacting protein in myocardial ischemia-reperfusion injury. J. Cardiovasc. Pharmacol. Ther. 2017;22:219–229. doi: 10.1177/1074248416675731. PubMed DOI PMC

Zhang C., He M., Ni L., He K., Su K., Deng Y., Li Y., Xia H. The role of arachidonic acid metabolism in myocardial ischemia-reperfusion injury. Cell Biochem. Biophys. 2020;78:255–265. doi: 10.1007/s12013-020-00928-z. PubMed DOI

Bartekova M., Adameova A., Gorbe A., Ferenczyova K., Pechanova O., Lazou A., Dhalla N.S., Ferdinandy P., Giricz Z. Natural and synthetic antioxidants targeting cardiac oxidative stress and redox signaling in cardiometabolic diseases. Free Radic. Biol. Med. 2021;169:446–477. doi: 10.1016/j.freeradbiomed.2021.03.045. PubMed DOI

Nagarajan N., Oka S., Sadoshima J. Modulation of signaling mechanisms in the heart by thioredoxin 1. Free Radic. Biol. Med. 2017;109:125–131. doi: 10.1016/j.freeradbiomed.2016.12.020. PubMed DOI PMC

Kleikers P.W.M., Wingler K., Hermans J.J.R., Diebold I., Altenhofer S., Radermacher K.A., Janssen B., Gorlach A., Schmidt H.H.H.W. NADPH oxidases as a source of oxidative stress and molecular target in ischemia/reperfusion injury. J. Mol. Med. 2012;90:1391–1406. doi: 10.1007/s00109-012-0963-3. PubMed DOI

Yang F., Smith M.J. Metal profiling in coronary ischemia-reperfusion injury: Implications for KEAP1/NRF2 regulated redox signaling. Free Radic. Biol. Med. 2024;210:158–171. doi: 10.1016/j.freeradbiomed.2023.11.013. PubMed DOI

Zhang P., Huang C., Liu H., Zhang M., Liu L., Zhai Y., Zhang J., Yang J., Yang J. The mechanism of the NFAT transcription factor family involved in oxidative stress response. J. Cardiol. 2024;83:30–36. doi: 10.1016/j.jjcc.2023.04.017. PubMed DOI

Zhang J., Pan W., Zhang Y., Tan M., Yin Y., Li Y., Zhang L., Han L., Bai J., Jiang T., et al. Comprehensive overview of Nrf2-related epigenetic regulations involved in ischemia-reperfusion injury. Theranostics. 2022;12:6626–6645. doi: 10.7150/thno.77243. PubMed DOI PMC

Sadrkhanloo M., Entezari M., Orouei S., Zabolian A., Mirzaie A., Maghsoudloo A., Raesi R., Asadi N., Hashemi M., Zarrabi A., et al. Targeting Nrf2 in ischemia-reperfusion alleviation: From signaling networks to therapeutic targeting. Life Sci. 2022;300:120561. doi: 10.1016/j.lfs.2022.120561. PubMed DOI

Mata A., Cadenas S. The antioxidant transcription factor Nrf2 in cardiac ischemia-reperfusion injury. Int. J. Mol. Sci. 2021;22:11939. doi: 10.3390/ijms222111939. PubMed DOI PMC

Yarmohammadi F., Hayes A.W., Karimi G. The cardioprotective effects of hydrogen sulfide by targeting endoplasmic reticulum stress and the Nrf2 signaling pathway: A review. Biofactors. 2021;47:701–712. doi: 10.1002/biof.1763. PubMed DOI

Ucar B.I., Ucar G., Saha S., Buttari B., Profumo E., Saso L. Pharmacological protection against ischemia-reperfusion injury by regulating the Nrf2-Keap1-ARE signaling pathway. Antioxidants. 2021;10:823. doi: 10.3390/antiox10060823. PubMed DOI PMC

Tavakoli R., Tabeshpour J., Asili J., Shakeri A., Sahebkar A. Cardioprotective effects of natural products via the Nrf2 signaling pathway. Curr. Vasc. Pharmacol. 2021;19:525–541. doi: 10.2174/1570161119999201103191242. PubMed DOI

Zhang X., Yu Y., Lei H., Cai Y., Shen J., Zhu P., He Q., Zhao M. The Nrf-2/HO-1 signaling axis: A ray of hope in cardiovascular diseases. Cardiol. Res. Pract. 2020;2020:5695723. doi: 10.1155/2020/5695723. PubMed DOI PMC

Kakavand H., Aghakouchakzadeh M., Coons J.C., Talasaz A.H. Pharmacologic prevention of myocardial ischemia-reperfusion injury in patients with acute coronary syndrome undergoing percutaneous coronary intervention. J. Cardiovasc. Pharmacol. 2021;77:430–449. doi: 10.1097/FJC.0000000000000980. PubMed DOI

Osorio-Llanes E., Villamizar-Villamizar W., Ospino Guerra M.C., Díaz-Ariza L.A., Castiblanco-Arroyave S.C., Medrano L., Mengual D., Belón R., Castellar-López J., Sepúlveda Y., et al. Effects of metformin on ischemia/reperfusion injury: New evidence and mechanisms. Pharmaceuticals. 2023;16:1121. doi: 10.3390/ph16081121. PubMed DOI PMC

Yang T., Zhang D. Research progress on the effects of novel hypoglycemic drugs in diabetes combined with myocardial ischemia/reperfusion injury. Ageing Res. Rev. 2023;86:101884. doi: 10.1016/j.arr.2023.101884. PubMed DOI

Dragasevic N., Jakovljevic V., Zivkovic V., Draginic N., Andjic M., Bolevich S., Jovic S. The role of aldosterone inhibitors in cardiac ischemia-reperfusion injury. Can. J. Physiol. Pharmacol. 2021;99:18–29. doi: 10.1139/cjpp-2020-0276. PubMed DOI

Ding X., Zhu C., Wang W., Li M., Ma C., Gao B. SIRT1 is a regulator of autophagy: Implications for the progression and treatment of myocardial ischemia-reperfusion. Pharmacol. Res. 2024;199:106957. doi: 10.1016/j.phrs.2023.106957. PubMed DOI

Lv J., Zhu X., Xing C., Chen Y., Bian H., Yin H., Gu X., Su L. Stimulator of interferon genes (STING): Key therapeutic targets in ischemia/reperfusion injury. Biomed. Pharmacother. 2023;167:115458. doi: 10.1016/j.biopha.2023.115458. PubMed DOI

Ding R., Wu W., Sun Z., Li Z. AMP-activated protein kinase: An attractive therapeutic target for ischemia-reperfusion injury. Eur. J. Pharmacol. 2020;888:173484. doi: 10.1016/j.ejphar.2020.173484. PubMed DOI

Wang J., Liu Y., Liu Y., Huang H., Roy S., Song Z., Guo B. Recent advances in nanomedicines for imaging and therapy of myocardial ischemia-reperfusion injury. J. Control Release. 2023;353:563–590. doi: 10.1016/j.jconrel.2022.11.057. PubMed DOI

Russo I., Barale C., Melchionda E., Penna C., Pagliaro P. Platelets and cardioprotection: The role of nitric oxide and carbon oxide. Int. J. Mol. Sci. 2023;24:6107. doi: 10.3390/ijms24076107. PubMed DOI PMC

Ryter S.W. Therapeutic potential of heme oxygenase-1 and carbon monoxide in acute organ injury, Critical illness, and inflammatory disorders. Antioxidants. 2020;9:1153. doi: 10.3390/antiox9111153. PubMed DOI PMC

Li T., Li Y., Zeng Y., Zhou X., Zhang S., Ren Y. Construction of preclinical evidence for propofol in the treatment of reperfusion injury after acute myocardial infarction: A systematic review and meta-analysis. Biomed. Pharmacother. 2024;174:116629. doi: 10.1016/j.biopha.2024.116629. PubMed DOI

Yue H., Zhang Q., Chang S., Zhao X., Wang M., Li W. Adiponectin protects against myocardial ischemia-reperfusion injury: A systematic review and meta-analysis of preclinical animal studies. Lipids Health Dis. 2024;23:51. doi: 10.1186/s12944-024-02028-w. PubMed DOI PMC

Chen K.Y., Liu Z., Lu J.H., Yang S.Y., Hu X.Y., Liang G.Y. The function of circular RNAs in myocardial ischemia-reperfusion injury: Underlying mechanisms and therapeutic advancement. Cardiovasc. Drugs Ther. 2024:1–12. doi: 10.1007/s10557-024-07557-1. PubMed DOI

Ge T., Ning B., Wu Y., Chen X., Qi H., Wang H., Zhao M. MicroRNA-specific therapeutic targets and biomarkers of apoptosis following myocardial ischemia-reperfusion injury. Mol. Cell. Biochem. 2024;479:2499–2521. doi: 10.1007/s11010-023-04876-z. PubMed DOI

Chang C., Cai R.P., Su Y.M., Wu Q., Su Q. Mesenchymal stem cell-derived exosomal noncoding RNAs as alternative treatments for myocardial ischemia-reperfusion injury: Current status and future perspectives. J. Cardiovasc. Transl. Res. 2023;16:1085–1098. doi: 10.1007/s12265-023-10401-w. PubMed DOI PMC

Su X., Zhou M., Li Y., Zhang J., An N., Yang F., Zhang G., Yuan C., Chen H., Wu H., et al. Protective effects of natural products against myocardial ischemia/reperfusion: Mitochondria-targeted therapeutics. Biomed. Pharmacother. 2022;149:112893. doi: 10.1016/j.biopha.2022.112893. PubMed DOI

Chen C., Yu L.T., Cheng B.R., Xu J.L., Cai Y., Jin J.L., Feng R.L., Xie L., Qu X.Y., Li D., et al. Promising therapeutic candidate for myocardial ischemia/reperfusion injury: What are the possible mechanisms and roles of phytochemicals? Front. Cardiovasc. Med. 2022;8:792592. doi: 10.3389/fcvm.2021.792592. PubMed DOI PMC

Mauerhofer C., Grumet L., Schemmer P., Leber B., Stiegler P. Combating ischemia-reperfusion injury with micronutrients and natural compounds during solid organ transplantation: Data of clinical trials and lessons of preclinical findings. Int. J. Mol. Sci. 2021;22:10675. doi: 10.3390/ijms221910675. PubMed DOI PMC

Yoshitomi T., Nagasaki Y. Self-assembling antioxidants for ischemia-reperfusion injuries. Antioxid. Redox Signal. 2022;36:70–80. doi: 10.1089/ars.2021.0103. PubMed DOI

Ertugrul I.A., van Suylen V., Damman K., de Koning M.L.Y., van Goor H., Erasmus M.E. Donor heart preservation with hydrogen sulfide: A systematic review and meta-analysis. Int. J. Mol. Sci. 2021;22:5737. doi: 10.3390/ijms22115737. PubMed DOI PMC

An N., Zhang G., Li Y., Yuan C., Yang F., Zhang L., Gao Y., Xing Y. Promising antioxidative effect of berberine in cardiovascular diseases. Front. Pharmacol. 2022;13:865353. doi: 10.3389/fphar.2022.865353. PubMed DOI PMC

Baliou S., Adamaki M., Ioannou P., Pappa A., Panayiotidis M.I., Spandidos D.A., Christodoulou I., Kyriakopoulos A.M., Zoumpourlis V. Protective role of taurine against oxidative stress. Mol. Med. Rep. 2021;24:605. doi: 10.3892/mmr.2021.12242. PubMed DOI PMC

Prem P.N., Sivakumar B., Boovarahan S.R., Kurian G.A. Recent advances in potential of Fisetin in the management of myocardial ischemia-reperfusion injury-A systematic review. Phytomedicine. 2022;101:154123. doi: 10.1016/j.phymed.2022.154123. PubMed DOI

Ferenczyova K., Kalocayova B., Bartekova M. Potential implications of quercetin and its derivatives in cardioprotection. Int. J. Mol. Sci. 2020;21:1585. doi: 10.3390/ijms21051585. PubMed DOI PMC

Sun Z., Wang X. Protective effects of polydatin on multiple organ ischemia-reperfusion injury. Bioorganic Chem. 2020;94:103485. doi: 10.1016/j.bioorg.2019.103485. PubMed DOI

Zheng H., Xu Y., Liehn E.A., Rusu M. Vitamin C as scavenger of reactive oxygen species during healing after myocardial infarction. Int. J. Mol. Sci. 2024;25:3114. doi: 10.3390/ijms25063114. PubMed DOI PMC

Shah A.K., Dhalla N.S. Effectiveness of some vitamins in the prevention of cardiovascular disease: A narrative review. Front. Physiol. 2021;12:729255. doi: 10.3389/fphys.2021.729255. PubMed DOI PMC

Kura B., Slezak J. The protective role of molecular hydrogen in ischemia/reperfusion injury. Int. J. Mol. Sci. 2024;25:7884. doi: 10.3390/ijms25147884. PubMed DOI PMC

Saengsin K., Sittiwangkul R., Chattipakorn S.C., Chattipakorn N. Hydrogen therapy as a potential therapeutic intervention in heart disease: From the past evidence to future application. Cell. Mol. Life Sci. 2023;80:174. doi: 10.1007/s00018-023-04818-4. PubMed DOI PMC

Li L., Li X., Zhang Z., Liu L., Zhou Y., Liu F. Protective mechanism and clinical application of hydrogen in myocardial ischemia-reperfusion injury. Pak. J. Biol. Sci. 2020;23:103–112. doi: 10.3923/pjbs.2020.103.112. PubMed DOI

Sun X., Wu S., Mao C., Qu Y., Xu Z., Xie Y., Jiang D., Song Y. Therapeutic potential of hydrogen sulfide in ischemia and reperfusion injury. Biomolecules. 2024;14:740. doi: 10.3390/biom14070740. PubMed DOI PMC

Gheitasi I., Akbari G., Savari F. Physiological and cellular mechanisms of ischemic preconditioning microRNAs-mediated in underlying of ischemia/reperfusion injury in different organs. Mol. Cell Biochem. 2025;480:855–868. doi: 10.1007/s11010-024-05052-7. PubMed DOI

Singh R.B., Hryshko L., Freed D., Dhalla N.S. Activation of proteolytic enzymes and depression of the sarcolemma Na+-K+-. ATPase in ischemia-reperfused heart may be mediated through oxidative stress. Can. J. Physiol. Pharmacol. 2012;90:249–260. doi: 10.1139/y11-128. PubMed DOI

Dixon I.M.C., Kaneko M., Hata T., Panagia V., Dhalla N.S. Alterations in cardiac membrane Ca2+ transport during oxidative stress. Mol. Cell. Biochem. 1990;99:125–133. doi: 10.1007/BF00230342. PubMed DOI

Matsubara T., Dhalla N.S. Effect of oxygen free radicals on cardiac contractile activity and sarcolemmal Na+-Ca2+ exchange. J. Cardiovasc. Pharmacol. Ther. 1996;1:211–218. doi: 10.1177/107424849600100304. PubMed DOI

Matsubara T., Dhalla N.S. Relationship between mechanical dysfunction and depression of sarcolemmal Ca2+-pump activity in hearts perfused with oxygen free radicals. Mol. Cell. Biochem. 1996;160/161:179–185. doi: 10.1007/BF00240048. PubMed DOI

Temsah R.M., Netticadan T., Chapman D., Takeda S., Mochizuki S., Dhalla N.S. Alterations in sarcoplasmic reticulum function and gene expression in ischemic-reperfused rat heart. Am. J. Physiol. 1999;277:H584–H594. doi: 10.1152/ajpheart.1999.277.2.H584. PubMed DOI

Makazan Z., Saini H.K., Dhalla N.S. Role of oxidative stress in alterations of mitochondrial function in ischemic-reperfused hearts. Am. J. Physiol. Heart Circ. Physiol. 2007;292:H1986–H1994. doi: 10.1152/ajpheart.01214.2006. PubMed DOI

Maddika S., Elimban V., Chapman D., Dhalla N.S. Role of oxidative stress in ischemia-reperfusion-induced alterations in myofibrillar ATPase activities and gene expression in the heart. Can. J. Physiol. Pharmacol. 2009;87:120–129. doi: 10.1139/Y08-105. PubMed DOI

Suzuki S., Kaneko M., Chapman D.C., Dhalla N.S. Alterations in cardiac contractile proteins due to oxygen free radicals. Biochim. Biophys. Acta. 1991;1074:95–100. doi: 10.1016/0304-4165(91)90045-I. PubMed DOI

Gajardo Cortez A.I.J., Lillo-Moya J., San-Martín-Martinez D., Pozo-Martinez J., Morales P., Prieto J.C., Aguayo R., Puentes Á., Ramos C., Silva S., et al. Safety and pharmacokinetics of a combined antioxidant therapy against myocardial reperfusion injury: A phase 1 randomized clinical trial in healthy humans. Clin. Pharmacol. Drug Dev. 2024;13:1051–1060. doi: 10.1002/cpdd.1443. PubMed DOI

Lagranha C.J., Deschamps A., Aponte A., Steenbergen C., Murphy E. Sex differences in the phosphorylation of mitochondrial proteins result in reduced production of reactive oxygen species and cardioprotection in females. Circ. Res. 2010;106:1681–1691. doi: 10.1161/CIRCRESAHA.109.213645. PubMed DOI PMC

Ciocci Pardo A., Scuri S., González Arbeláez L.F., Caldiz C., Fantinelli J., Mosca S.M. Survival kinase-dependent pathways contribute to gender difference in the response to myocardial ischemia-reperfusion and ischemic post-conditioning. Cardiovasc. Pathol. 2018;33:19–26. doi: 10.1016/j.carpath.2017.12.003. PubMed DOI

Murphy E., Steenbergen C. Gender-based differences in mechanisms of protection in myocardial ischemia-reperfusion injury. Cardiovasc. Res. 2007;75:478–486. doi: 10.1016/j.cardiores.2007.03.025. PubMed DOI

Milerová M., Drahota Z., Chytilová A., Tauchmannová K., Houštěk J., Ošťádal B. Sex difference in the sensitivity of cardiac mitochondrial permeability transition pore to calcium load. Mol. Cell. Biochem. 2016;412:147–154. doi: 10.1007/s11010-015-2619-4. PubMed DOI

Ostadal B., Drahota Z., Houstek J., Milerova M., Ostadalova I., Hlavackova M., Kolar F. Developmental and sex differences in cardiac tolerance to ischemia-reperfusion injury: The role of mitochondria 1. Can. J. Physiol. Pharmacol. 2019;97:808–814. doi: 10.1139/cjpp-2019-0060. PubMed DOI

Cross H.R., Murphy E., Steenbergen C. Ca2+ loading and adrenergic stimulation reveal male/female differences in susceptibility to ischemia-reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 2002;283:H481–H489. doi: 10.1152/ajpheart.00790.2001. PubMed DOI

Ross J.L., Howlett S.E. Age and ovariectomy abolish beneficial effects of female sex on rat ventricular myocytes exposed to simulated ischemia and reperfusion. PLoS ONE. 2012;7:e38425. doi: 10.1371/journal.pone.0038425. PubMed DOI PMC

Zhao B., Peng J., Chen C., Fan Y., Zhang K., Zhang Y., Huang X. Innovative engineering of superoxide dismutase for enhanced cardioprotective biocatalysis in myocardial ischemia-reperfusion injury. Int. J. Biol. Macromol. 2025;286:137656. doi: 10.1016/j.ijbiomac.2024.137656. PubMed DOI

Tanno S., Yamamoto K., Kurata Y., Adachi M., Inoue Y., Otani N., Mishima M., Yamamoto Y., Kuwabara M., Ogino K., et al. Protective effects of topiroxostat on an ischemia-reperfusion model of rat hearts. Circ. J. 2018;82:1101–1111. doi: 10.1253/circj.CJ-17-1049. PubMed DOI

Elgebaly S.A., Poston R., Todd R., Helmy T., Almaghraby A.M., Elbayoumi T., Kreutzer D.L. Cyclocreatine protects against ischemic injury and enhances cardiac recovery during early reperfusion. Expert Rev. Cardiovasc. Ther. 2019;17:683–697. doi: 10.1080/14779072.2019.1662722. PubMed DOI

Curran J., Burkhoff D., Kloner R.A. Beyond reperfusion: Acute ventricular unloading and cardioprotection during myocardial infarction. J. Cardiovasc. Transl. Res. 2019;12:95–106. doi: 10.1007/s12265-019-9863-z. PubMed DOI PMC

Stoian L., Krüger M., Schmitt J., Kleinbongard P. Is there an effect of ischemic conditioning on myocardial contractile function following acute myocardial ischemia/reperfusion injury? Biochim. Biophys. Acta Mol. Basis Dis. 2019;1865:822–830. doi: 10.1016/j.bbadis.2018.12.020. PubMed DOI

Skrzypiec-Spring M., Urbaniak J., Sapa-Wojciechowska A., Pietkiewicz J., Orda A., Karolko B., Danielewicz R., Bil-Lula I., Woźniak M., Schulz R., et al. Matrix metalloproteinase-2 inhibition in acute ischemia-reperfusion heart injury-cardioprotective properties of carvedilol. Pharmaceuticals. 2021;14:1276. doi: 10.3390/ph14121276. PubMed DOI PMC

Ferrari R., Balla C., Malagù M., Guardigli G., Morciano G., Bertini M., Biscaglia S., Campo G. Reperfusion damage- A story of success, failure, and hope. Circ. J. 2017;81:131–141. doi: 10.1253/circj.CJ-16-1124. PubMed DOI

Huang J., Li R., Wang C. The role of mitochondrial quality control in cardiac ischemia/reperfusion injury. Oxidative Med. Cell. Longev. 2021;2021:5543452. doi: 10.1155/2021/5543452. PubMed DOI PMC

Moris D., Spartalis M., Tzatzaki E., Spartalis E., Karachaliou G.S., Triantafyllis A.S., Karaolanis G.I., Tsilimigras D.I., Theocharis S. The role of reactive oxygen species in myocardial redox signaling and regulation. Ann. Transl. Med. 2017;5:324. doi: 10.21037/atm.2017.06.17. PubMed DOI PMC

Buja L.M. Myocardial ischemia and reperfusion injury. Cardiovasc. Pathol. 2005;14:170–175. doi: 10.1016/j.carpath.2005.03.006. PubMed DOI

Aliev G., Obrenovich M.E., Seyidova D., de la Torre J.C. Exploring ischemia-induced vascular lesions and potential pharmacological intervention strategies. Histol. Histopathol. 2005;20:261–273. PubMed

Zhang W.Z., Li R., Liu S., Zhang J.D., Ning X.F., Cai S.L. Effects of renal ischemic postconditioning on myocardial ultrastructural organization and myocardial expression of Bcl-2/Bax in rabbits. BioMed Res. Int. 2016;2016:9349437. doi: 10.1155/2016/9349437. PubMed DOI PMC

Lee K.H., Ha S.J., Woo J.S., Lee G.J., Lee S.R., Kim J.W., Park H.K., Kim W. Exenatide prevents morphological and structural changes of mitochondria following ischaemia-reperfusion injury. Heart Lung Circ. 2017;26:519–523. doi: 10.1016/j.hlc.2016.08.007. PubMed DOI

Shirakawa M., Imura H., Nitta T. Propofol protects the immature rabbit heart against ischemia and reperfusion injury: Impact on functional recovery and histopathological changes. BioMed Res. Int. 2014;2014:601250. doi: 10.1155/2014/601250. PubMed DOI PMC

Tung C., Varzideh F., Farroni E., Mone P., Kansakar U., Jankauskas S.S., Santulli G. Elamipretide: A review of its structure, mechanism of action, and therapeutic potential. Int. J. Mol. Sci. 2025;26:944. doi: 10.3390/ijms26030944. PubMed DOI PMC

Guo Z., Tian Y., Gao J., Zhou B., Zhou X., Chang X., Zhou H. Enhancement of mitochondrial homeostasis: A novel approach to attenuate hypoxic myocardial injury. Int. J. Med. Sci. 2024;21:2897–2911. doi: 10.7150/ijms.103986. PubMed DOI PMC

Consolini A.E., Ragone M.I., Bonazzola P., Colareda G.A. Mitochondrial bioenergetics during ischemia and reperfusion. Adv. Exp. Med. Biol. 2017;982:141–167. PubMed

Zhao Z.Q. Oxidative stress-elicited myocardial apoptosis during reperfusion. Curr. Opin. Pharmacol. 2004;4:159–165. doi: 10.1016/j.coph.2003.10.010. PubMed DOI

Du B., Fu Q., Yang Q., Yang Y., Li R., Yang X., Yang Q., Li S., Tian J., Liu H. Different types of cell death and their interactions in myocardial ischemia-reperfusion injury. Cell Death Discov. 2025;11:87. doi: 10.1038/s41420-025-02372-5. PubMed DOI PMC

Tsurusaki S., Kizana E. Mechanisms and therapeutic potential of multiple forms of cell death in myocardial ischemia-reperfusion injury. Int. J. Mol. Sci. 2024;25:13492. doi: 10.3390/ijms252413492. PubMed DOI PMC

Shen Y., Liu X., Shi J., Wu X. Involvement of Nrf2 in myocardial ischemia and reperfusion injury. Int. J. Biol. Macromol. 2019;125:496–502. doi: 10.1016/j.ijbiomac.2018.11.190. PubMed DOI

Boengler K., Eickelmann C., Kleinbongard P. Mitochondrial kinase signaling for cardioprotection. Int. J. Mol. Sci. 2024;25:4491. doi: 10.3390/ijms25084491. PubMed DOI PMC

Cadenas S. ROS and redox signaling in myocardial ischemia-reperfusion injury and cardioprotection. Free Radic. Biol. Med. 2018;117:76–89. doi: 10.1016/j.freeradbiomed.2018.01.024. PubMed DOI

Zhong Y., Li X.Y., Liang T.J., Ding B.Z., Ma K.X., Ren W.X., Liang W.J. Effects of NLRP3 inflammasome mediated pyroptosis on cardiovascular diseases and intervention mechanism of Chinese medicine. Chin. J. Integr. Med. 2024;30:468–479. doi: 10.1007/s11655-024-3655-2. PubMed DOI

Zhang Y.S., Lu L.Q., Jiang Y.Q., Li N.S., Luo X.J., Peng J.W., Peng J. Allopurinol attenuates oxidative injury in rat hearts suffered ischemia/reperfusion via suppressing the xanthine oxidase/vascular peroxidase 1 pathway. Eur. J. Pharmacol. 2021;908:174368. doi: 10.1016/j.ejphar.2021.174368. PubMed DOI

Becerra R., Román B., Di Carlo M.N., Mariangelo J.I., Salas M., Sanchez G., Donoso P., Schinella G.R., Vittone L., Wehrens X.H., et al. Reversible redox modifications of ryanodine receptor ameliorate ventricular arrhythmias in the ischemic-reperfused heart. Am. J. Physiol. Heart Circ. Physiol. 2016;311:H713–H724. doi: 10.1152/ajpheart.00142.2016. PubMed DOI PMC

Yang F., Jiang X., Cao H., Shuai W., Zhang L., Wang G., Quan D., Jiang X. Daphnetin preconditioning decreases cardiac injury and susceptibility to ventricular arrhythmia following ischaemia-reperfusion through the TLR4/MyD88/NF-κb signalling pathway. Pharmacology. 2021;106:369–383. doi: 10.1159/000513631. PubMed DOI PMC

Abdulsalam T.M., Hasanin A.H., Mohamed R.H., El Sayed Badawy A. Angiotensin receptor-neprilysin inhibitior (thiorphan/irbesartan) decreased ischemia-reperfusion induced ventricular arrhythmias in rat; in vivo study. Eur. J. Pharmacol. 2020;882:173295. doi: 10.1016/j.ejphar.2020.173295. PubMed DOI

Das B., Sarkar C. Cardiomyocyte mitochondrial KATP channels participate in the antiarrhythmic and antiinfarct effects of KATP activators during ischemia and reperfusion in an intact anesthetized rabbit model. Pol. J. Pharmacol. 2003;55:771–786. PubMed

Involvement of Oxidative Stress in Mitochondrial Abnormalities During the Development of Heart Disease