The Protection of Nebivolol Against Isoproterenol-Induced Cardiac Damage and the Role of Irisin

Öz

Background: Nebivolol (NEB) is a β blocker that effectively relaxes the vessels while blocking adrenoreceptors. It is known that irisin dysfunction plays a role in cardiovascular diseases such as hypertension, coronary artery disease, and myocardial infarction. This study aimed to evaluate the effects of nebivolol treatment in isoproterenol (ISO) -induced cardiac damage on the levels of irisin, which is known to be effective in cardiomyocytes where brown fat tissue is abundant, malondialdehyde (MDA), an oxidative stress indicator, and creatine kinase myocardial band (CK-MB), which is released into the blood from cardiomyocytes due to myocardial damage. Materials and Methods: 28 Sprague-Dawley male rats were distributed to control, ISO, ISO+NEB and NEB groups. Isoproterenol 150 mg/kg was given subcutaneously twice with an interval of 24 hours, and nebivolol 10 mg/kg/day was given via gavage for 10 days. Irisin and CK-MB were measured by ELISA, and MDA by spectrophotometric method. Results: Serum CK-MB, heart tissue MDA and serum irisin levels increased significantly with ısoproterenol induction. Nebivolol treatment significantly reduced all three parameters (p<0.05). Conclusions: Although further studies are needed, it is thought that irisin may play a role in ISO-induced cardiac damage and nebivolol protection.

Anahtar Kelimeler

• Cardiac damage
• Isoproterenol
• Irisin
• Nebivolol

Nebivololün İsoproterenol İndüklü Kardiyak Hasarda Koruyuculuğu ve İrisinin Rolü

Öz

Amaç: Nebivolol (NEB), adrenoreseptör blokajı yaparken beraberinde damarlarda etkin bir gev-şeme sağlayan bir β blokördür. İrisin disfonksiyonunun hipertansiyon, koroner arter hastalığı, miyokard infarktüsü gibi kardiyovasküler hastalıklarda rolü olduğu bilinmektedir. Bu çalışmada isoproterenol (İSO) ile indüklenmiş kardiyak hasarda nebivolol tedavisinin, kahverengi yağ doku-sunun bol bulunduğu kardiyomiyositlerde etkin olduğu bilinen irisin, oksidatif stres göstergesi malondialdehit (MDA) ve miyokard hasarına bağlı kardiyomiyositlerden kana salınan kreatin kinaz miyokart bandı (CK-MB) seviyelerine etkilerinin değerlendirilmesi amaçlanmıştır. Materyal ve metod: 28 adet Sprague-Dawley erkek sıçan kontrol, ISO, ISO+NEB ve NEB grupları-na dağıtıldı. İsoproterenol 150 mg/kg subkutan 24 saat ara ile subkutan yolla 2 kez uygulandı, nebivolol 10 gün süreyle 10 mg/kg/gün gavaj yoluyla verildi. İrisin ve CK-MB ELISA, MDA ise spektrofotometrik yöntem ile ölçüldü. Bulgular: Serum CK-MB, kalp dokusu MDA ve serum irisin düzeyleri İSO indüklemesi ile anlamlı arttı. Nebivolol tedavisi ise her üç parametreyi de anlamlı şekilde azalttı (p<0.05). Sonuç: Daha ileri çalışmalara ihtiyaç olmakla beraber, irisinin İSO indüklü kardiyak hasarda ve nebivolol koruyuculuğunda rolü olabileceği düşünülmektedir.

Anahtar Kelimeler

• ardkoşullama
• irisin
• izoproterenol
• kardiyak İR
• nebivolol

Destekleyen Kurum

Fırat Üniversitesi BAP Koordinasyon Birimi tarafından karşılanmıştır.

Etik Beyan

Bu makalede sunulan veriler, bilgiler ve dokümanlar akademik ve etik kurallar çerçevesinde elde edilmiş ve sunulmuştur. Kullanılan verilerde herhangi bir değişiklik yapılmamıştır. Projenin ilk etik beyanında yer alan hocamızın, projeden feragat dilekçesi paylaşılmıştır. Dr.Öğr.Üyesi Merve YILMAZ BOZOĞLAN, MD 16.07.2024

Teşekkür

Fırat Üniversitesi BAP Koordinasyon Merkezine teşekkür ederiz.

Kaynakça

1. 1. Chrysant SG, Chrysant GS. Antihypertensive and cardiopro-tective effects of three generations of beta-adrenergic bloc-kers: an historical perspective. Hosp Pract. 2022;50(3):196-202.
2. 2. Taddei S, Tsabedze N, Tan RS. β-blockers are not all the same: pharmacologic similarities and differences, potential combinations and clinical implications. Curr Med Res Opin. 2024;40(sup1):15-23.
3. 3. Tao S, Huang J, Xiao J, Ke G, Fu P. Cardio-selective versus non-selective β-blockers for cardiovascular events and mor-tality in long-term dialysis patients: A systematic review and meta-analysis. PLoS One. 2022;17(12):e0279171.
4. 4. do Vale GT, Ceron CS, Gonzaga NA, Simplicio JA, Padovan JC. Three Generations of β-blockers: History, Class Differences and Clinical Applicability. Curr Hypertens Rev. 2019;15(1):22-31.
5. 5. Munzel T, Gori T. Nebivolol: the somewhat-different beta adrenergic receptor blocker. J Am Coll Cardiol. 2009;54:1491–9.
6. 6. Tzemos N, Lim PO, MacDonald TM. Nebivolol reverses en-dothelial dysfunction in essential hypertension: a randomi-zed, double-blind, crossover study. Circulation 2001;104(5):511-4.
7. 7. Weiss R. Nebivolol: a novel beta-blocker with nitric oxide-induced vasodilatation. Vasc Health Risk Manag. 2006;2(3):303-8.
8. 8. Simon G, Johnson ML. Comparison of antihypertensive and B1-adrenoreceptor antagonist effect of nebivolol and ateno-lol in essential hypertension. Clin Exper Hypertens. 1993;15:501–

9. 9. Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, et al. Global Burden of Cardiovascular Disea-ses and Risk Factors, 1990-2019: Update From the GBD 2019 Study. J Am Coll Cardiol. 2020;76(25):2982-3021.
10. 10. Estell EG, Le PT, Vegting Y, Kim H, Wrann C, Bouxsein ML, et al. Irisin directly stimulates osteoclastogenesis and bone resorption in vitro and in vivo. Elife. 2020;9:e58172.
11. 11. Arıkan Ş, Akın G. İrisin ve egzersiz. Türk Spor Bilimleri Dergi-si. 2019; 2(2): 106-114.
12. 12. Ho MY, Wang CY. Role of Irisin in Myocardial Infarction, Heart Failure, and Cardiac Hypertrophy. Cells. 2021;10(8):2103.
13. 13. Kalkan F, Parlakpinar H, Disli OM, Tanriverdi LH, Ozhan O, Polat A, et al. Protective and therapeutic effects of dexpant-henol on isoproterenol-induced cardiac damage in rats. J Cell Biochem. 2018;119(9):7479-7489.
14. 14. Varagic J, Ahmad S, Voncannon JL, Moniwa N, Simington SW Jr, Brosnihan BK, et al. Nebivolol reduces cardiac angiotensin II, associated oxidative stress and fibrosis but not arterial pressure in salt-loaded spontaneously hypertensive rats. J Hypertens. 2012 Sep;30(9):1766-74.
15. 15. Hosseini A, Rajabian A, Sobhanifar MA, Alavi MS, Taghipour Z, Hasanpour M, et al. Attenuation of isoprenaline-induced myocardial infarction by Rheum turkestanicum. Biomed Pharmacother. 2022;148:112775.
16. 16. Goldsborough E 3rd, Osuji N, Blaha MJ. Assessment of Car-diovascular Disease Risk: A 2022 Update. Endocrinol Metab Clin North Am. 2022;51(3):483-509.
17. 17. Malik S, Goyal S, Ojha SK, Bharti S, Nepali S, Kumari S, et al. Seabuckthorn attenuates cardiac dysfunction and oxidative stress in isoproterenol-induced cardiotoxicity in rats. Int J Toxicol. 2011;30(6):671-680.
18. 18. Ulla A, Mohamed MK, Sikder B, Rahman AT, Sumi FA, Hos-sain M, et al. Coenzyme Q10 prevents oxidative stress and fibrosis in isoprenaline induced cardiac remodeling in aged rats. BMC Pharmacol Toxicol. 2017;18(1):29.
19. 19. Maffei A, Lembo G. Nitric oxide mechanisms of nebivolol. Ther Adv Cardiovasc Dis. 2009;3(4):317-27.
20. 20. Al-Amir H, Janabi A, Hadi NR. Ameliorative effect of nebivo-lol in doxorubicin-induced cardiotoxicity. J Med Life. 2023;16(9):1357-1363.
21. 21. Toblli J, Cao G, Rivas C, Munoz M, Giani J, Dominici F, et al. Cardiovascular protective effects of nebivolol in Zucker dia-betic fatty rats. J Hypertens. 2010 May;28(5):1007-19.
22. 22. Inselmann G, Köhler K, Lange V, Silber R, Nellessen U. Lipid peroxidation and cardiac troponin T release during routine cardiac surgery. Cardiology. 1998;89(2):124-9.
23. 23. Al-Amir H, Janabi A, Hadi NR. Ameliorative effect of nebivo-lol in doxorubicin-induced cardiotoxicity. J Med Life. 2023;16(9):1357-1363.
24. 24. do Vale GT, da Silva CBP, Sousa AH, Gonzaga NA, Parente JM, Araújo KM, et al. Nebivolol Prevents Up-Regulation of Nox2/NADPH Oxidase and Lipoperoxidation in the Early Sta-ges of Ethanol-Induced Cardiac Toxicity. Cardiovasc Toxicol. 2021;21(3):224-235.
25. 25. Liu JF, Su G, Chen LX, Zhou JP, Gao J, Zhang JJ, et al. Irisin Attenuates Apoptosis Following Ischemia-Reperfusion Injury Through Improved Mitochondria Dynamics and ROS Suppres-sion Mediated Through the PI3K/Akt/mTOR Axis. Mol Neu-robiol. 2023;60(8):4261-4272.
26. 26. Ho MY, Wen MS, Yeh JK, Hsieh IC, Chen CC, Hsieh MJ, et al. Excessive irisin increases oxidative stress and apoptosis in murine heart. Biochem Biophys Res Commun. 2018;503(4):2493-2498.
27. 27. Hsieh IC, Ho MY, Wen MS, Chen CC, Hsieh MJ, Lin CP, et al. Serum irisin levels are associated with adverse cardiovascu-lar outcomes in patients with acute myocardial infarction. Int J Cardiol. 2018;261:12-17.
28. 28. Hirayama K, Ishii H, Kikuchi R, Suzuki S, Aoki T, Harada K, et al. Clinical Impact of Circulating Irisin on Classified Coronary Plaque Characteristics. J Appl Lab Med. 2018;3:79–88.
29. 29. Kuloglu T, Aydin S, Eren MN, Yilmaz M, Sahin I, Kalayci M, et al. Irisin: a potentially candidate marker for myocardial in-farction. Peptides. 2014;55:85-91.
30. 30. He J, Hou L, Liu Q, Zhou R. Irisin links Claudin-5 preservation and Mfn2-mediated mitochondrial dynamics to resist doxorubicin-induced cardiac endothelial damage. Biochem Biophys Res Commun. 2024;696:149501.
31. 31. Grzeszczuk M, Dzięgiel P, Nowińska K. The role of FNDC5/Irisin in cardiovascular disease. Cells. 2024;13(3):277.