Melatonin enhanced the cardioprotective effects of HTK solution on Langendorff-perfused mouse hearts subjected to ischemia/reperfusion

Document Type : Original Article

Authors

1 Institute of Medical Research, Northwestern Polytechnical University, Xi’an Shaanxi, 710072 China

2 Department of Physiology and Pathophysiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, 710032 China

3 Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China

4 Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China

Abstract

Objective(s): Cardiac arrest is a crucial procedure in various cardiac surgeries, during which the heart is subjected to an ischemic state. The occurrence of ischemia/reperfusion (I/R) injury is inevitable due to aortic blockage and opening. The Histidine-tryptophan-ketoglutarate (HTK) solution is commonly used as an organ protection liquid to mitigate cardiac injury during cardiac surgery. Despite its widespread use, there is significant potential for improving its protective efficacy.
Materials and Methods: The cardioprotective effect of HTK solution with and without melatonin was evaluated using the isolated Langendorff-perfused mouse heart model. The isolated C57bL/6 mouse hearts were randomly divided into four groups: control, I/R, HTK solution treatment before reperfusion (HTK+I/R), and HTK solution combined with melatonin before reperfusion (HTK+M+I/R). Cardiac function and myocardial injury markers were then measured. AMP-activated protein kinase α2 (AMPKα2) KO mice were used to investigate the underlying mechanism.
Results: In our study, we found that melatonin significantly improved the protective effects of HTK solution in an isolated Langendorff-perfused mouse model, mechanistically by reducing mitochondrial damage, improving energy metabolism, inhibiting cardiomyocyte apoptosis, and reducing myocardial infarction size. We also observed that the HTK solution alone was ineffective in inhibiting ER stress, but when melatonin was added, there was a significant reduction in ER stress. Furthermore, melatonin was found to alleviate carbonyl stress during cardiac I/R. Interestingly, our results showed that the cardioprotective properties of melatonin were dependent on AMPKα2.
Conclusion: The findings presented in this study offer a valuable empirical foundation for the development of perioperative cardioprotective strategies.

Keywords

Main Subjects

References

1. Mokbel M, Zamani H, Lei I, Chen YE, Romano MA, Aaronson KD, et al. Histidine-tryptophan-ketoglutarate solution for donor heart preservation is safe for transplantation. Ann Thorac Surg 2020; 109:763-770.
2. Reynolds AC, Asopa S, Modi A, King N. HTK versus multidose cardioplegias for myocardial protection in adult cardiac surgery: A meta-analysis. J Card Surg 2021; 36:1334-1343.
3. Albadrani M. Histidine-tryptophan-ketoglutarate solution versus multidose cardioplegia for myocardial protection in cardiac surgeries: A systematic review and meta-analysis. J Cardiothorac Surg 2022; 17:133-147.
4. Wu B, Yu L, Wang Y, Wang H, Li C, Yin Y, et al. Aldehyde dehydrogenase 2 activation in aged heart improves the autophagy by reducing the carbonyl modification on SIRT1. Oncotarget 2016; 7:2175-2188.
5. Ji MJ, Son KH, Hong JH. Addition of oh8dG to cardioplegia attenuated myocardial oxidative injury through the inhibition of sodium bicarbonate cotransporter activity. Antioxidants (Basel) 2022;11:1641-1657.
6. Holeček M. Histidine in health and disease: Metabolism, physiological importance, and use as a supplement. Nutrients 2020;12:848-867.
7. Rauen U, de Groot H. Inherent toxicity of organ preservation solutions to cultured hepatocytes. Cryobiology 2008; 56:88-92.
8. Yousefi B, Reiter RJ. Melatonin in health and diseases. Biochimie 2022; 202:1.
9. Mauriz JL, Collado PS, Veneroso C, Reiter RJ, González-Gallego J. A review of the molecular aspects of melatonin’s anti-inflammatory actions: Recent insights and new perspectives. J Pineal Res 2013;54:1-14.
10. Coskun A, Yegen C, Arbak S, Attaallah W, Gunal O, Elmas MA, et al. Melatonin in preservation solutions prevents ischemic injury in rat kidneys. PloS One 2022; 17:e0273921-e0273940.
11. Ma H, Wang J, Thomas DP, Tong C, Leng L, Wang W, et al. Impaired macrophage migration inhibitory factor-AMP-activated protein kinase activation and ischemic recovery in the senescent heart. Circulation 2010; 122:282-292.
12. Huang R, Xu Y, Lu X, Tang X, Lin J, Cui K, et al. Melatonin protects inner retinal neurons of newborn mice after hypoxia-ischemia. J Pineal Res 2021; 71:e12716.
13. Miller EJ, Li J, Leng L, McDonald C, Atsumi T, Bucala R, et al. Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart. Nature 2008; 451:578-582.
14. Ma H, Guo R, Yu L, Zhang Y, Ren J. Aldehyde dehydrogenase 2 (ALDH2) rescues myocardial ischaemia/reperfusion injury: Role of autophagy paradox and toxic aldehyde. Eur Heart J 2011; 32:1025-1038.
15. Gu C, Xing Y, Jiang L, Chen M, Xu M, Yin Y, et al. Impaired cardiac SIRT1 activity by carbonyl stress contributes to aging-related ischemic intolerance. PloS One 2013; 8:e74050-74060.
16. Chitimus DM, Popescu MR, Voiculescu SE, Panaitescu AM, Pavel B, Zagrean L, et al. Melatonin’s impact on antioxidative and anti-inflammatory reprogramming in homeostasis and disease. Biomolecules 2020;10:1211-1238.
17. Gombert M, Codoñer-Franch P. Melatonin in early nutrition: Long-term effects on cardiovascular system. Int J Mol Sci 2021;22:6809-6825.
18. Petrosillo G, Colantuono G, Moro N, Ruggiero FM, Tiravanti E, Di Venosa N, et al. Melatonin protects against heart ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Am J Physiol Heart Circ Physiol 2009; 297:H1487-H1493.
19. Liu LF, Qin Q, Qian ZH, Shi M, Deng QC, Zhu WP, et al. Protective effects of melatonin on ischemia-reperfusion induced myocardial damage and hemodynamic recovery in rats. Eur Rev Med Pharmacol Sci 2014; 18:3681-3686.
20. Yu L, Liang H, Lu Z, Zhao G, Zhai M, Yang Y, et al. Membrane receptor-dependent Notch1/Hes1 activation by melatonin protects against myocardial ischemia-reperfusion injury: In vivo and in vitro studies. J Pineal Res 2015; 59:420-433.
21. Yang Z, Li C, Wang Y, Yang J, Yin Y, Liu M, et al. Melatonin attenuates chronic pain related myocardial ischemic susceptibility through inhibiting RIP3-MLKL/CaMKII dependent necroptosis. J Mol Cell Cardiol 2018; 125:185-194.
22. Kaneko S, Okumura K, Numaguchi Y, Matsui H, Murase K, Mokuno S, et al. Melatonin scavenges hydroxyl radical and protects isolated rat hearts from ischemic reperfusion injury. Life Sci 2000; 67:101-112.
23. Lochner A, Genade S, Davids A, Ytrehus K, Moolman JA. Short- and long-term effects of melatonin on myocardial post-ischemic recovery. J Pineal Res 2006; 40:56-63.
24. Genade S, Genis A, Ytrehus K, Huisamen B, Lochner A. Melatonin receptor-mediated protection against myocardial ischaemia/reperfusion injury: Role of its anti-adrenergic actions. J Pineal Res 2008; 45:449-458.
25. Schaefer M, Gebhard M-M, Gross W. The effect of melatonin on hearts in ischemia/reperfusion experiments without and with HTK cardioplegia. Bioelectrochemistry 2019; 129:170-178.
26. Reiter RJ, Tan D-X. Melatonin: A novel protective agent against oxidative injury of the ischemic/reperfused heart. Cardiovasc Res 2003; 58:10-19.
27. Schaefer M, Gebhard M-M, Gross W. The efficiency of heart protection with HTK or HTK-N depending on the type of ischemia. Bioelectrochemistry 2019; 125:58-69.
28. Vazan R, Pancza D, Béder I, Styk J. Ischemia-reperfusion injury--antiarrhythmic effect of melatonin associated with reduced recovering of contractility. Gen Physiol Biophys 2005; 24:355-359.
29. Ytrehus K, Liu Y, Tsuchida A, Miura T, Liu GS, Yang XM, et al. Rat and rabbit heart infarction: effects of anesthesia, perfusate, risk zone, and method of infarct sizing. Am J Physiol 1994; 267:H2383-H2390.
30. Garg AD, Kaczmarek A, Krysko O, Vandenabeele P, Krysko DV, Agostinis P. ER stress-induced inflammation: Does it aid or impede disease progression? Trends Mol Med 2012; 18:589-598.
31. Nakajima S, Hiramatsu N, Hayakawa K, Saito Y, Kato H, Huang T, et al. Selective abrogation of BiP/GRP78 blunts activation of NF-κB through the ATF6 branch of the UPR: Involvement of C/EBPβ and mTOR-dependent dephosphorylation of Akt. Mol Cell Biol 2011; 31:1710-1718.
32. Hosoi T, Honda M, Oba T, Ozawa K. ER stress upregulated PGE₂/IFNγ-induced IL-6 expression and down-regulated iNOS expression in glial cells. Sci Rep 2013; 3:3388-3393.
33. Verma G, Bhatia H, Datta M. JNK1/2 regulates ER-mitochondrial Ca2+ cross-talk during IL-1β-mediated cell death in RINm5F and human primary β-cells. Mol Biol Cell 2013; 24:2058-2071.
34. Cui J, Zhang F, Wang Y, Liu J, Ming X, Hou J, et al. Macrophage migration inhibitory factor promotes cardiac stem cell proliferation and endothelial differentiation through the activation of the PI3K/Akt/mTOR and AMPK pathways. Int J Mol Med 2016; 37:1299-1309.
35. Russell RR, Li J, Coven DL, Pypaert M, Zechner C, Palmeri M, et al. AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest 2004; 114:495-503.
36. Chin JT, Troke JJ, Kimura N, Itoh S, Wang X, Palmer OP, et al. A novel cardioprotective agent in cardiac transplantation: metformin activation of AMP-activated protein kinase decreases acute ischemia-reperfusion injury and chronic rejection. Yale J Biol Med 2011; 84:423-432.
37. Timmermans AD, Balteau M, Gélinas R, Renguet E, Ginion A, de Meester C, et al. A-769662 potentiates the effect of other AMP-activated protein kinase activators on cardiac glucose uptake. Am J Physiol Heart Circ Physiol 2014; 306:H1619-H1630.
38. Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, et al. Distinct roles of autophagy in the heart during ischemia and reperfusion: Roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res 2007; 100:914-922.
39. Dong Y, Zhang M, Liang B, Xie Z, Zhao Z, Asfa S, et al. Reduction of AMP-activated protein kinase alpha2 increases endoplasmic reticulum stress and atherosclerosis in vivo. Circulation 2010; 121:792-803.
40. Hu L, Zhou L, Wu X, Liu C, Fan Y, Li Q. Hypoxic preconditioning protects cardiomyocytes against hypoxia/reoxygenation injury through AMPK/eNOS/PGC-1α signaling pathway. Int J Clin  Exp Pathol 2014; 7:7378-7388.
41. Gonon AT, Widegren U, Bulhak A, Salehzadeh F, Persson J, Sjöquist P-O, et al. Adiponectin protects against myocardial ischaemia-reperfusion injury via AMP-activated protein kinase, Akt, and nitric oxide. Cardiovasc Res 2008; 78:116-122.
42. Lagneux C, Joyeux M, Demenge P, Ribuot C, Godin-Ribuot D. Protective effects of melatonin against ischemia-reperfusion injury in the isolated rat heart. Life Sci 2000; 66:503-509.
43. Mathes AM, Wolf B, Rensing H. Melatonin receptor antagonist luzindole is a powerful radical scavenger in vitro. J Pineal Res 2008; 45:337-338.
44. Stroethoff M, Christoph I, Behmenburg F, Raupach A, Bunte S, Senpolat S, et al. Melatonin receptor agonist ramelteon reduces ischemia-reperfusion injury through activation of mitochondrial potassium channels. J Cardiovasc Pharmacol 2018; 72:106-111.
Iranian Journal of Basic Medical Sciences
Volume 27, Issue 3
March 2024
Pages 366-374

Files

Share

How to cite

Statistics