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

Öz

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.

Anahtar Kelimeler

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

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

Öz

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.

Anahtar Kelimeler

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

Kaynakça

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