Sıçanlarda uzun süreli iskemi-reperfüzyon modelinde N-asetil sistein ve trimetazidin'in S100b, oksidatif stres ve apoptozis üzerindeki etkisi
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Date
2013
Authors
Şentürk, Tunay
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Publisher
Uludağ Üniversitesi
Abstract
Miyokardiyal iskemi reperfüzyon hasarının etyolojisinde reaktif oksijen radikalleri önemli rol oynar. İskemi reperfüzyona bağlı kardiyak miyosit ölümü kabaca nekroz ve apoptosis olarak sınıflandırılmıştır. İnfarkt gelişmiş miyokardda erken dönemdeki başlıca ölüm şekli apoptozistir. Bu çalışmanın amacı, sıçanlarda miyokardiyal iskemi reperfüzyon modelinde Nasetil sistein ve trimetazidinin tek başına ya da kombinasyonunun oksidatif stres, infarkt alanı ve apoptozis üzerindeki üzerindeki etkisinin incelenmesiydi. Miyokard iskemisi, sol ön inen koroner arter ligasyonu ile gerçekleştirildi. İskemik periyodun ortasında tuzlu su (1 ml/kg) veya NAS (50, 150 mg/kg) TMZ (3, 5 mg/kg) intravenöz yolla uygulandı. Sıçanlarda deney boyunca kardiyovasküler parametreler kaydedildi. Reperfüzyon döneminden sonra sıçanların kalpleri çıkarıldı, apoptosis ve nekroz incelemeleri için boyama yapıldı. İnfarkt büyüklüğü, infarkt alanının risk alanına oranlanmasıyla değerlendirildi. Apoptozis aktivasyonu, kaspaz 3 ve TUNEL yöntemleriyle değerlendirildi. Serum M30, M65, S100b ve malondialdehid ölçümleri için sıçanlardan kan örnekleri alındı. Hem TMZ, hemde NAS’in, tuzlu su grubuna göre oksidatif stresi ve infarkt alanını anlamlı olarak azalttığı saptandı (p<0.001). Bunun yanında TMZ’in her iki dozunda, NAS’e göre oksidatif stres (p<0.05) ve infarkt alanında daha belirgin azalmaya neden olduğu izlendi (p<0.001). Ayrıca, NAS ve TMZ’in benzer şekilde apoptotik aktivitede azalmaya neden olduğu, NAS ve TMZ kombinasyonunun apoptotik aktiviteyi, sadece TMZ kullanan gruplara göre daha anlamlı şekilde azalttığı izlendi (p<0.05). Çalışma grupları arasında, serum S100B düzeyleri ile apoptozis belirteci olan serum M30, M65 düzeylerinde ise arasında anlamlı farklılık saptanmamıştır (p>0.05). Çalışmanın sonuçları sıçanlarda uzun süreli iskemi reperfüzyon modelinde İV yolla verilen NAS ve TMZ’in oksidatif stresi azalttığı ve apoptotik aktiviteyi azalttığını göstermiştir. Apoptotik aktivitedeki en belirgin azalma NAS ve TMZ’in birlikte verildiği grupta izlenmiştir. Miyokardiyal reperfüzyonu sağlamaya yönelik mekanik girişimler yanında farklı III noktaları hedefleyen hücre koruyucu ajanların kullanımı reperfüzyon hasarının, reperfüzyona bağlı morbiditenin azaltılmasına yarar sağlayabilir.
Reactive oxygen species (ROS) play an important role in the etiology of myocardial ischemia reperfusion (IR) injury. IR-induced cardiac myocyte death has been broadly classified as occurring by either necrosis or apoptosis. Apoptosis is the early and predominant form of cell death in infarcted myocardium. The aim of the study was to investigate the effect of trimetazidine and N-acetylcysteine, used alone or in combination, on oxidative stress, infarct size, and IR-induced cardiomyocyte apoptosis in a rat model of myocardial IR. Myocardial ischemia was established by ligating the left anterior descending artery (LAD). Saline (1 ml/kg) or NAC (50, 150 mg/kg), TMZ (3, 5 mg/kg) were intravenously injected in the middle of the ischemic period. Cardiovascular parameters were recorded throughout the experimental period. At the end of the reperfusion, the hearts were removed and heart sections were subsequently stained to determine necrosis and apoptosis. The infarct size was evaluated as the ratio of the infarct area to the risk area. Apoptotic activation was assessed by a caspase-3 immunostaining and TUNEL assay. In addition, blood samples were collected from the animals to measure serum M30, M65, S100b and malondialdehyde levels. Both TMZ and NAC significantly reduced oxidative stress and infarct area compared to the saline group (p<0.001). In addition, both TMZ doses reduced oxidative stress (p<0.05) and infarct area to a higher extent compared to NAC (p<0.001). Similarly, the combination of NAC and TMZ reduced apoptotic activity; the combination of NAC and TMZ reduced apoptotic activity more significantly compared to TMZ-only group (p<0.001). There was no significant difference in serum S100B levels, and serum M30 and M65 levels, which are apoptotic markers (p>0.05). V Intravenous NAC and TMZ administration decreased oxidative stress and apoptotic activity in a long-term IR model in rats. The most significant decrease in apoptotic activity was observed in the NAC+TMZ-treated group. In addition to mechanical attempts to secure myocardial reperfusion, using cell-protective agents may help to decrease reperfusion injury and reperfusion-associated morbidity.
Reactive oxygen species (ROS) play an important role in the etiology of myocardial ischemia reperfusion (IR) injury. IR-induced cardiac myocyte death has been broadly classified as occurring by either necrosis or apoptosis. Apoptosis is the early and predominant form of cell death in infarcted myocardium. The aim of the study was to investigate the effect of trimetazidine and N-acetylcysteine, used alone or in combination, on oxidative stress, infarct size, and IR-induced cardiomyocyte apoptosis in a rat model of myocardial IR. Myocardial ischemia was established by ligating the left anterior descending artery (LAD). Saline (1 ml/kg) or NAC (50, 150 mg/kg), TMZ (3, 5 mg/kg) were intravenously injected in the middle of the ischemic period. Cardiovascular parameters were recorded throughout the experimental period. At the end of the reperfusion, the hearts were removed and heart sections were subsequently stained to determine necrosis and apoptosis. The infarct size was evaluated as the ratio of the infarct area to the risk area. Apoptotic activation was assessed by a caspase-3 immunostaining and TUNEL assay. In addition, blood samples were collected from the animals to measure serum M30, M65, S100b and malondialdehyde levels. Both TMZ and NAC significantly reduced oxidative stress and infarct area compared to the saline group (p<0.001). In addition, both TMZ doses reduced oxidative stress (p<0.05) and infarct area to a higher extent compared to NAC (p<0.001). Similarly, the combination of NAC and TMZ reduced apoptotic activity; the combination of NAC and TMZ reduced apoptotic activity more significantly compared to TMZ-only group (p<0.001). There was no significant difference in serum S100B levels, and serum M30 and M65 levels, which are apoptotic markers (p>0.05). V Intravenous NAC and TMZ administration decreased oxidative stress and apoptotic activity in a long-term IR model in rats. The most significant decrease in apoptotic activity was observed in the NAC+TMZ-treated group. In addition to mechanical attempts to secure myocardial reperfusion, using cell-protective agents may help to decrease reperfusion injury and reperfusion-associated morbidity.
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Keywords
Miyokard, Reperfüzyon hasarı, Apoptosis, Oksidatif stress, S100b, Myocardium, Reperfusion injury, Oxidative stress
Citation
Şentürk, T. (2013). Sıçanlarda uzun süreli iskemi-reperfüzyon modelinde N-asetil sistein ve trimetazidin'in S100b, oksidatif stres ve apoptozis üzerindeki etkisi. Yayınlanmamış doktora tezi. Uludağ Üniversitesi Sağlık Bilimleri Enstitüsü.