Cardioprotective Effects of Insulin-Like Growth Factor (Igf-1) in A Rat Model of Myocarditis

Year 2024, Volume: 46 Issue: 6, 945 - 954, 07.11.2024

Erinç Yücel , Münevver Nazlıcan Zengin , Özlem Özmen , Osman Çiftçi

https://doi.org/10.20515/otd.1552820

Abstract

Doxorubicin is widely used in the treatment of various solid tumors. Despite its potent antineoplastic activity, doxorubicin's use is limited due to its cardiotoxic effects. This study aimed to evaluate the protective role of insulin-like growth factor (IGF)-1 in doxorobusin-induced cardiotoxicity. Thirty-two rats were divided into 4 groups: Control, Doxorubicin (4 mg/kg/week), IGF-1 (1 µg /kg every 2 days), doxorubicin (4 mg/kg/week)+ IGF-1 (1 µg /kg every 2 days). Doxorubicin and IGF-1 were administered intraperitoneally. After four weeks of drug administration, heart and blood samples were taken under anesthesia. In biochemical analyses, CK-MB and Troponin-I levels were measured in blood serum. TAS, TOS, TNF-α, and IL-6 levels in heart tissue were measured by ELISA method. iNOS, HIF-1α, SERCA2a, LC3, Beclin-1 and SQSTM1 mRNA expression levels were analyzed by RT-PCR. Histological and immunohistochemical (Caspase-3 and ICAM-1) analyses were performed. Doxorubicin decreased heart rate, tail blood pressure and increased serum CK-MB and Troponin-I levels. Doxorubicin shifted the total antioxidant/oxidant balance in favor of oxidants in heart tissue and caused an increase in TNF-α and IL-6 cytokine levels. Doxorubicin increased HIF-1α, SERCA2a, LC3, Beclin-1 and SQSTM1 mRNA expression levels in heart tissue. It caused histological damage and severe Caspase-3 and ICAM-1 expressions in rat heart tissue. Co-administration with IGF-1 reduced the toxic effects of doxorubicin. It was concluded that IGF-1 could improve doxorubicin-induced cardiotoxicity through antioxidant, anti-inflammatory and antiapoptotic effects.

Keywords

Doxorubicin, IGF-1, Myocarditis, Oxidative Damage, Autophage

Project Number

2021SABE015

Doksorubusin Kaynaklı Kardiyotoksisite Modelinde İnsülin Benzeri Büyüme Faktörünün (IGF-1) Etkisinin Araştırılması

Abstract

Doksorubisin, çeşitli katı tümörlerin tedavisinde yaygın olarak kullanılmaktadır. Doksorubisin güçlü antineoplastik aktivitesine rağmen kardiyotoksik etkisi nedeniyle kullanımı sınırlıdır. Bu çalışmada doksorobusin kaynaklı kardiyotoksisitede insülin benzeri büyüme faktörünü (IGF)-1 koruyucu rolünü değerlendirilmesi amaçlandı. Otuz iki adet sıçan 4 gruba ayrıldı: Kontrol, Doksorubisin (4 mg/kg/hafta), IGF-1 (2 günde bir 1 µg /kg), doksorubisin (4 mg/kg/hafta)+ IGF-1 (2 günde bir 1 µg /kg).Doksorubisin ve IGF-1 intraperitoneal olarak uygulandı. Dört hafta süren ilaç uygulamalarının ardında anestezi altında kalp ve kan örnekleri alındı. Biyokimyasal analizlerde kan serumundan CK-MB ve Troponin-I seviyeleri ölçüldü. Kalp dokusunda TAS, TOS, TNF-α, ve IL-6 düzeyleri ELISA yöntemiyle ölçüldü. iNOS, HIF-1α, SERCA2a, LC3, Beclin-1 ve SQSTM1 mRNA ekpresyon düzeyleri RT-PCR ile analiz edildi. Histolojik ve immünohistokimyasal (Kaspaz-3 ve ICAM-1) analizler yapıldı. Doksorubisin kalp hızını azaltırken kuyruk kan basıncını düşürdü ve serum CK-MB ve Troponin-I seviyelerini artırdı. Doksorubisin kalp dokusunda total antioksidan/oksidan dengeyi oksidan lehine çevirdi ve TNF-α ve IL-6 sitokin seviyelerinde artışa neden oldu. Doksorobusin kalp dokusunda HIF-1α, SERCA2a, LC3, Beclin-1 ve SQSTM1 mRNA ekpresyon düzeylerini artırdı. Sıçan kalp dokusunda histolojik hasara ve şiddetli Kaspaz-3 ve ICAM-1 ekpresyonlarına neden oldu. IGF-1’ ile birlikte uygulanması doksorubisin toksik etkilerini azalttı. IGF-1’in antioksidan, antiinflamatuar ve antiapoptotik etkilerle doksorubisin kaynaklı kardiyotoksisiteyi iyileştirebileceğini sonucuna ulaşıldı.

Keywords

Doksorubusin, IGF-1, Miyokardit, Oksidatif Hasar, Otofaji

Supporting Institution

PAU BİLİMSEL ARAŞTIRMA PROJELERİ

Project Number

2021SABE015

References

• 1. Rivankar S: An overview of doxorubicin formulations in cancer therapy. J Cancer Res Ther 10: 853–858, 2014.
• 2. Kalivendi, S. V., Kotamraju, S., Zhao, H., Joseph, J., & Kalyanaraman, B. (2001). Doxorubicin-induced apoptosis is associated with increased transcription of endothelial nitric-oxide synthase: effect of antiapoptotic antioxidants and calcium. Journal of Biological Chemistry, 276(50), 47266-47276.
• 3. Mitry MA, Edwards JG: Doxorubicin induced heart failure: Phenotype and molecular mechanisms. IJC Heart & Vasculature 10: 17–24, 2016.
• 4. Shakir DK, Rasul KI: Chemotherapy Induced Cardiomyopathy: Pathogenesis, Monitoring and Management. J Clin Med Res 1: 8, 2009.
• 5. Sheibani M, Azizi Y, Shayan M, Nezamoleslami S, Eslami F, Farjoo MH, Dehpour AR: Doxorubicin-Induced Cardiotoxicity: An Overview on Pre-clinical Therapeutic Approaches. Cardiovasc Toxicol 22: 292–310, 2022.
• 6. Syahputra RA, Harahap U, Dalimunthe A, Nasution MP and Satria D: The Role of Flavonoids as a Cardioprotective Strategy against Doxorubicin-Induced Cardiotoxicity: A Review. Molecules 2022, Vol 27, Page 1320 27: 1320, 2022.
• 7. Yu J, Wang C, Kong Q, Wu X, Lu JJ, Chen X: Recent progress in doxorubicin-induced cardiotoxicity and protective potential of natural products. Phytomedicine 40: 125–139, 2018.
• 8. Conchillo, M., Prieto, J., & Quiroga, J. (2007). Factor de crecimiento semejante a la insulina tipo I (IGF-I) y cirrosis hepática. Revista española de enfermedades digestivas, 99(3), 156-164.
• 9. Macvanin M, Gluvic Z, Radovanovic J, Essack M, Gao X, Isenovic ER: New insights on the cardiovascular effects of IGF-1. Front Endocrinol (Lausanne) 14: 1142644, 2023.
• 10. Higashi Y, Gautam S, Delafontaine P, Sukhanov S: IGF-1 and cardiovascular disease. Growth Hormone & IGF Research 45: 6–16, 2019.
• 11. Boudina S: Cardiac Aging and Insulin Resistance: Could Insulin/Insulin-Like Growth Factor (IGF) Signaling be used as a Therapeutic Target?
• 12. Kciuk M, Gielecińska A, Mujwar S, Kołat D, Kałuzińska-Kołat Ż, Celik I and Kontek R: Doxorubicin—An Agent with Multiple Mechanisms of Anticancer Activity. Cells 2023, Vol 12, Page 659 12: 659, 2023.
• 13. Kong CY, Guo Z, Song P, et al.: Underlying the Mechanisms of Doxorubicin-Induced Acute Cardiotoxicity: Oxidative Stress and Cell Death. Int J Biol Sci 18: 760, 2022.
• 14. Koss-Mikołajczyk I, Todorovic V, Sobajic S, Mahajna J, Gerić M, Tur JA, Bartoszek A: Natural Products Counteracting Cardiotoxicity during Cancer Chemotherapy: The Special Case of Doxorubicin, a Comprehensive Review. International Journal of Molecular Sciences 2021, Vol 22, Page 10037 22: 10037, 2021.
• 15. Syahputra RA, Harahap U, Dalimunthe A, Nasution MP, Satria D: The Role of Flavonoids as a Cardioprotective Strategy against Doxorubicin-Induced Cardiotoxicity: A Review. Molecules 2022, Vol 27, Page 1320 27: 1320, 2022.
• 16. Sádaba MC, Martín-Estal I, Puche JE, Castilla-Cortázar I: Insulin-like growth factor 1 (IGF-1) therapy: Mitochondrial dysfunction and diseases. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1862: 1267–1278, 2016.
• 17. Conti E, Musumeci M, Assenza G, Quarta G, Autore C, Volpe M: Recombinant human insulin-like growth factor-1: a new cardiovascular disease treatment option? Cardiovasc Hematol Agents Med Chem 6: 258–271, 2008.
• 18. Bhagat A, Kleinerman ES: Anthracycline-Induced Cardiotoxicity: Causes, Mechanisms, and Prevention. Adv Exp Med Biol 1257: 181–192, 2020.
• 19. Rawat PS, Jaiswal A, Khurana A, Bhatti JS and Navik U: Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management. Biomedicine & Pharmacotherapy 139: 111708, 2021.
• 20. Weinstein DM, Mihm M, Bauer J: Cardiac peroxynitrite formation and left ventricular dysfunction following doxorubicin treatment in mice. Journal of Pharmacology and Experimental Therapeutics, 2000.
• 21. Ramos, P. J. (2018). IGF-1 as a Target in Emerging Heart Failure Therapeutics (Master's thesis, The University of Arizona).
• 22. Higashi Y, Gautam S, Delafontaine P, Sukhanov S: IGF-1 and Cardiovascular Disease.
• 23. Ma S, Li X, Dong L, Zhu J, Zhang H, Jia Y: Protective effect of Sheng-Mai Yin, a traditional Chinese preparation, against doxorubicin-induced cardiac toxicity in rats. BMC Complement Altern Med 16: 1–10, 2016.
• 24. Hilal MA, Mahmoud SED, Shokry MM, Said AM: Predictive Role of Cardiac Troponin I, Creatine Kinase-Mb and Electrocardiogram in Early Assessment of Acute Cardiotoxicity in Patients Poisoned by Cardiotoxic Drugs and Toxins. Cardiology and Angiology: An International Journal: 18–30, 2020.
• 25. Liao Y, Li H, Pi Y, Li Z, Jin S: Cardioprotective effect of IGF-1 against myocardial ischemia/reperfusion injury through activation of PI3K/Akt pathway in rats in vivo. J Int Med Res 47: 3886–3897, 2019.
• 26. Rose NR: Critical Cytokine Pathways to Cardiac Inflammation. https://home.liebertpub.com/jir 31: 705–710, 2011.
• 27. Durdagi G, Pehlivan DY, Oyar EO, Bahceci SA, Ozbek M: Effects of Melatonin and Adrenomedullin in Reducing the Cardiotoxic Effects of Doxorubicin in Rats. Cardiovasc Toxicol 21: 354–364, 2021.
• 28. Kim YS, Sung SH, Tang Y, et al.: Protective Effect of Taurine on Mice with Doxorubicin-induced Acute Kidney Injury. Adv Exp Med Biol 975: 1191–1201, 2017.
• 29. Renu K, V.G. A, Tirupathi TP, Arunachalam S: Molecular mechanism of doxorubicin-induced cardiomyopathy – An update. Eur J Pharmacol 818: 241–253, 2018.
• 30. Morón, Ú. M., & Castilla-Cortázar, I. (2012). Protection against oxidative stress and “IGF-I deficiency conditions”. Antioxidant enzyme, 3, 1135-1140.
• 31. Sahu BD, Kumar JM, Kuncha M, Borkar RM, Srinivas R and Sistla R: Baicalein alleviates doxorubicin-induced cardiotoxicity via suppression of myocardial oxidative stress and apoptosis in mice. Life Sci 144: 8–18, 2016.
• 32. Wang XL, Liu HR, Tao L, et al.: Role of iNOS-derived reactive nitrogen species and resultant nitrative stress in leukocytes-induced cardiomyocyte apoptosis after myocardial ischemia/reperfusion. Apoptosis 12: 1209–1217, 2007.
• 33. Zepeda AB, Pessoa A, Castillo RL, Figueroa CA, Pulgar VM and Farías JG: Cellular and molecular mechanisms in the hypoxic tissue: role of HIF-1 and ROS. Cell Biochem Funct 31: 451–459, 2013.
• 34. Bonello S, Zähringer C, BelAiba RS, et al.: Reactive oxygen species activate the HIF-1α promoter via a functional NFκB site. Arterioscler Thromb Vasc Biol 27: 755–761, 2007.
• 35. Jiang B, Zhou X, Yang T, et al.: The role of autophagy in cardiovascular disease: Cross-interference of signaling pathways and underlying therapeutic targets. Front Cardiovasc Med 10: 1088575, 2023.
• 36. Lipskaia L, Chemaly ER, Hadri L, Lompre AM, Hajjar RJ: Sarcoplasmic reticulum Ca2+ ATPase as a therapeutic target for heart failure. Expert Opin Biol Ther 10: 29, 2010.
• 37. Obradovic M, Zafirovic S, Soskic S, Stanimirovic J, Trpkovic A, Jevremovic D, Isenovic ER: Effects of IGF-1 on the Cardiovascular System. researchgate.net 25: 3715–3725, 2019.
• 38. Cove-Smith L, Woodhouse N, Hargreaves A, et al.: An Integrated Characterization of Serological, Pathological, and Functional Events in Doxorubicin-Induced Cardiotoxicity. Toxicological Sciences 140: 3–15, 2014.
• 39. Aziz MM, Abd El Fattah MA, Ahmed KA, Sayed HM: Protective effects of olmesartan and l-carnitine on doxorubicin-induced cardiotoxicity in rats. https://doi.org/101139/cjpp-2019-0299 98: 183–193, 2019.
• 40. Hu, L. F., Lan, H. R., Li, X. M., & Jin, K. T. (2021). A Systematic Review of the Potential Chemoprotective Effects of Resveratrol on Doxorubicin‐Induced Cardiotoxicity: Focus on the Antioxidant, Antiapoptotic, and Anti‐Inflammatory Activities. Oxidative medicine and cellular longevity, 2021(1), 2951697.