Effects of long- and short-term darbepoetin-alpha treatment on oxidative stress, inflammation and endothelial injury in ApoE knockout mice

Abstract

Background. Atherosclerosis and atherosclerosis-related complications are the main cause of death in the world. Vascular injury in response to inflammation and enhanced oxidant stress promotes endothelial dysfunction and leads to atherosclerotic lesions. Objectives. Low-dose treatment with darbepoetin-alpha may be a potential therapeutic tool for endothelial injury and atherosclerosis. Material and methods. In order to study the effect of darbepoetin-alpha on endothelial injury and atherosclerosis, we used ApoE(-/-)mice as the atherosclerotic mice model. We monitored atherosclerosis and plaque formation histochemically in ApoE knockout mice at early and late stages of atherosclerosis. Darbepoetin-alpha was injected intraperitoneally at a dose of 0.1 mu g/kg to ApoE(-/-)mice. The results of 2 ApoE(-/-)mice groups injected with darbepoetin-alpha (early and late stages of atherosclerosis) were compared to the results of the corresponding saline injected ApoE(-/-)mice groups and the control (C57BL/6) mice. Results. Lipid profile (total cholesterol, triglyceride), inflammation (CRP, IL-6, histamine), endothelial injury (ICAM-1, selectin) and oxidative stress markers (lipid peroxidation, protein oxidation) were significantly increased in 4 atherosclerotic groups compared to the control group. Short-term darbepoetin-alpha had no marked effects on indicators of inflammation and endothelial injury in the ApoE knockout mice groups compared to the ApoE knockout mice not treated with darbepoetin-alpha, however, darbepoetin-alpha significantly decreased 8-isoprostane and protein carbonyl content. Long term darbepoetin-alpha treatment reduced oxidative stress in ApoE(-/-)mice. Conclusions. This study contributes to understanding and elucidating the biochemical changes occurring during early and late stages of atherosclerosis development regarding lipid profile, inflammation, endothelial injury and oxidative stress markers.