Effects of combo therapy with coenzyme Q10 and mitochondrial transplantation on myocardial ischemia/reperfusion-induced arrhythmias in aged rats

Document Type : Original Article

Authors

1 Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

2 Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran

3 Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

4 Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran 2 Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran

5 Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

10.22038/ijbms.2024.80092.17348

Abstract

Objective(s): Ischemia/reperfusion (IR)-induced ventricular arrhythmia, which mainly occurs after the opening of coronary artery occlusion, poses a clinical problem. This study aims to investigate the effectiveness of pretreatment with coenzyme Q10 (CoQ10) in combination with mitochondrial transplantation on IR-induced ventricular arrhythmias in aged rats.
Materials and Methods: Myocardial IR induction was performed by left anterior descending coronary artery occlusion for 30 min, followed by re-opening for 24 hr. CoQ10 was administered intraperitoneally at a dosage of 10 mg/kg/day for two weeks before inducing IR. At the start of reperfusion, 500 µl of the respiration buffer containing 6×106±5×105 mitochondria/ml of respiration buffer harvested from the pectorals major muscle of young donor rats were injected intramyocardially. To investigate arrhythmias, the heart’s electrical activity during ischemia and the first 30 min of reperfusion were recorded by electrocardiogram. After 24 hr of reperfusion, cardiac histopathological changes, creatine kinase-MB, nitric oxide metabolites (NOx), oxidative stress markers (malondialdehyde, total anti-oxidant, superoxide dismutase, and glutathione peroxidase), and the expression of genes regulating mitochondrial fission/fusion were measured.
Results: Pretreatment with CoQ10 in combination with mitochondrial transplantation reduced ventricular arrhythmias, cardiac histopathological changes, and creatine kinase-MB levels. Simultaneously, this combined therapeutic approach increased myocardial NOx levels, fostering an improved oxidative balance. It also triggered the down-regulation of mitochondrial fission genes, coupled with the up-regulation of mitochondrial fusion genes. 
Conclusion: The combination of CoQ10 and mitochondrial transplantation demonstrated a notable anti-arrhythmic effect by elevating NOx levels, reducing oxidative stress, and improving mitochondrial fission/fusion in aged rats with myocardial IRI.

Keywords

Main Subjects

References

1. Rodgers JL, Jones J, Bolleddu SI, Vanthenapalli S, Rodgers LE, Shah K,  et al. Cardiovascular risks associated with gender and aging. J Cardiovasc Dev Dis 2019; 6:19-36.
2. Pagan LU, Gomes MJ, Gatto M, Mota GAF, Okoshi K, Okoshi MP. The role of oxidative stress in the aging heart. Antioxidants (Basel) 2022; 11:336-353. 
3. Poznyak AV, Kirichenko TV, Borisov EE, Shakhpazyan NK, Kartuesov AG, Orekhov AN. Mitochondrial implications in cardiovascular aging and diseases: the specific role of mitochondrial dynamics and shifts. Int J Mol Sci 2022; 23:2951-2963.
4. HeuschG, Myocardial ischaemia-reperfusion injury and cardioprotection in perspective. Nat Rev Cardiol 2020; 17:773-789.
5. Bhar-Amato J, Davies W, Agarwal SW. Ventricular arrhythmia after acute myocardial infarction: The perfect storm. Arrhythm Electrophysiol Rev 2017; 6:134-139.
6. Saadeh K, Fazmin IT. Mitochondrial dysfunction increases arrhythmic triggers and substrates; potential anti-arrhythmic pharmacological targets. Front Cardiovasc Med 2021; 8:646932.
7. Schneider AM, Özsoy M, Zimmermann FA, Feichtinger RG, Mayr JA, Kofler B, et al. Age-related deterioration of mitochondrial function in the intestine. Oxid Med Cell Longev 2020; 2020:4898217.
8. Wu NN, Zhang Y, Ren J, Mitophagy, mitochondrial dynamics, and homeostasis in cardiovascular aging. Oxid Med Cell Longev 2019; 2019:9825061.
9. Dhalla NS, Shah AK, Adameova A, Bartekova M. Role of oxidative stress in cardiac dysfunction and subcellular defects due to ischemia-reperfusion injury. Biomedicines 2022; 10: 1473-1491.
10. Adameova A, Shah AK, Dhalla NS. Role of oxidative stress in the genesis of ventricular arrhythmias. Int J Mol Sci 2020; 21:4200
11. Yang Q, Ai W, Nie L, Yan C, WuS. Vildagliptin reduces myocardial ischemia-induced arrhythmogenesis via modulating inflammatory responses and promoting expression of genes regulating mitochondrial biogenesis in rats with type-II diabetes. J Interv Card Electrophysiol 2020; 59:517-526.
12. Bermudez-Gonzalez JL, Sanchez-Quintero D, Proaño-Bernal L, Santana-Apreza R, Jimenez-Chavarria MA, Luna-Alvarez-Amezquita J A, et al. Role of the anti-oxidant activity of melatonin in myocardial ischemia-reperfusion injury. Antioxidants (Basel) 2022; 11:627-647.
13. Sun M, Jiang W, Mu N, Zhang Z, Yu L, Ma H. Mitochondrial transplantation as a novel therapeutic strategy for cardiovascular diseases. J Transl Med 2023; 21:347-4805.
14. Hayashida K, Takegawa R, Shoaib M, Aoki T, Choudhary RC, Kuschner CE, et al. Mitochondrial transplantation therapy for ischemia reperfusion injury: a systematic review of animal and human studies. J Transl Med 2021; 19:214-228.
15. Liang S, Ping Z, Gej. Coenzyme q10 regulates anti-oxidative stress and autophagy in acute myocardial ischemia-reperfusion injury. Oxid Med Cell Longev 2017; 2017:9863181.
16. Noh, Y.H., Kim KY, Shim MS, Choi SH, Choi S, Ellisman MH. Inhibition of oxidative stress by coenzyme q10 increases mitochondrial mass and improves bioenergetic function in optic nerve head astrocytes. Cell Death Dis 2013; 4: e820.
17. Singh RB, Wander GS, Rastogi A, Shukla PK, Mittal A, Sharma JP, et al. Randomized, double-blind placebo-controlled trial of coenzyme q10 in patients with acute myocardial infarction. Cardiovasc Drugs Ther 1998; 12:347-353.
18. Barcelos IP, Haas RH. Coq10 and aging. Biology (Basel). 2019; 8:28-49.
19. Bafadam S, Mokhtari B, Vafaee MS, Oscuyi ZZ, Nemati S, Badalzadeh R. Mitochondrial transplantation combined with coenzyme Q10 induces cardioprotection and mitochondrial improvement in aged male rats with reperfusion injury. Exp Physiol 2024; 109: ep091358
20. Eleawa SM, Alkhateeb M, Ghosh S, Al-Hashem F, Shatoor AS, Alhejaily A, Khalil MA. Coenzyme Q10 protects against acute consequences of experimental myocardial infarction in rats. Int J Physiol Pathophysiol Pharmacol 2015; 7:1-13.
21. Jabbari H, Roushandeh AM, Rostami MK, Razavi-Toosi MT, Shokrgozar MA, Jahanian-Najafabadi A, et al. Mitochondrial transplantation ameliorates ischemia/reperfusion-induced kidney injury in rat. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165809.
22. Mousavi K, Manthari RK, Najibi A, Jia Z, Ommati MM, Heidari R. Mitochondrial dysfunction and oxidative stress are involved in the mechanism of tramadol-induced renal injury. Curr Res Pharmacol Drug Discov 2021; 2:100049.
23. Díaz-Vesga MC, Zúñiga-Cuevas Ú, Ramírez-Reyes A, Herrera-Zelada N, Palomo I, Bravo-Sagua R, Riquelme JA. Potential therapies to protect the aging heart against ischemia/reperfusion injury. Front Cardiovasc Med 2021; 8:770421.
24. Curtis MJ, Hancox JC, Farkas A, Wainwright C L, Stables C L, Saint D A. The lambeth conventions (II): Guidelines for the study of animal and human ventricular and supraventricular arrhythmias. Pharmacol Ther 2013; 139:213-248.
25. Najafi M, Noroozi E, Javadi A, Badalzadeh Rl. Anti-arrhythmogenic and anti-inflammatory effects of troxerutin in ischemia/reperfusion injury of diabetic myocardium. Biomed Pharmacother 2018; 102:385-391.
26. Curtis MJ, Walker MJ. Quantification of arrhythmias using scoring systems: An examination of seven scores in an in vivo model of regional myocardial ischaemia. Cardiovasc Res 1988; 22:656-665.
27. Habibi P, Alihemmati A, Ahmadiasl N, Fateh A, Anvari E. Exercise training attenuates diabetes-induced cardiac injury through increasing miR-133a and improving pro-apoptosis/anti-apoptosis balance in ovariectomized rats. Iran J Basic Med Sci 2020; 23:79-85.
28. Janero DR. Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free Radic Biol Med 1990; 9:515-540.
29. Miranda KM, Espey MG, Winkv DA. A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide 2001; 5:62-71.
30. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method. Methods 2001; 25:402-408.
31. Hosseini L, Vafaee MS, Mahmoudi J, Badalzadeh R. Nicotinamide adenine dinucleotide emerges as a therapeutic target in aging and ischemic conditions. Biogerontology 2019; 20:381-395.
32. Awad AM, Bradley MC, Fernández-Del-Río L, Nag A, Tsui HS, Clarke CF. Coenzyme q10 deficiencies: pathways in yeast and humans. Essays Biochem 2018; 62:361-376.
33. Kowalczyk P, Sulejczak D, Kleczkowska P, Bukowska-Ośko I, Kucia M, Popiel M, et al. Mitochondrial oxidative stress-a causative factor and therapeutic target in many diseases. Int J Mol Sci 2021; 22:13384.
34. Kent AC, El-Baradie KBY, Hamrick MW. Targeting the mitochondrial permeability transition pore to prevent age-associated cell damage and neurodegeneration. Oxid Med Cell Longev 2021; 2021:6626484.
35. Reno-Bernstein CM, Oxspring M, Bayles J, Huang EY, Holiday I, Fisher SJ. Vitamin E treatment in insulin-deficient diabetic rats reduces cardiac arrhythmias and mortality during severe hypoglycemia. Am J Physiol Endocrinol Metab 2022; 323:428-434.
36. Menezes-Rodrigues FS, Errante PR, Araújo EA, Fernandes MPP, Silva MMD, Pires-Oliveira M, et al. Cardioprotection stimulated by resveratrol and grape products prevents lethal cardiac arrhythmias in an animal model of ischemia and reperfusion. Acta Cir Bras 2021; 36:e360306.
37. Lu J, Meng Y, Wang R, Zhang R. Anti-arrhythmogenic effects of quercetin postconditioning in myocardial ischemia/reperfusion injury in a rat model. J King Saud Univ Sci 2020; 32:1910-1916.
38. Walewska A, Szewczyk A, Koprowski P. Gas signaling molecules and mitochondrial potassium channels. Int J Mol Sci 2018; 19:3227-2346.
39. Badalzadeh R, Yousefi B, Majidinia M, Ebrahimi H. Anti-arrhythmic effect of diosgenin in reperfusion-induced myocardial injury in a rat model: Activation of nitric oxide system and mitochondrial KATP channel. J Physiol Sci 2014; 64:393-400.
40. 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.
41. Maneechote C, Palee S, Chattipakorn SC, Chattipakorn N. Roles of mitochondrial dynamics modulators in cardiac ischaemia/reperfusion injury. J Cell Mol Med 2017; 21:2643-2653.
42. Ramirez-Barbieri G, Moskowitzova K, Shin B, Blitzer D, Orfany A, Guariento A, et al. Alloreactivity and allorecognition of syngeneic and allogeneic mitochondria. Mitochondrion 2019; 46:103-115.
Iranian Journal of Basic Medical Sciences
Volume 28, Issue 1
January 2025
Pages 38-48

Files

Share

How to cite

Statistics