Early atherosclerosis development in female apolipoprotein E-deficient mice is associated with an increased vascular oxidative stress

Abstract

Livan Delgado-Roche, Yanet Hernandez, Ivonilce Venturi, Irina Wilkins, Dalia Alvarez

Objective: The mechanisms of atherosclerosis development in the apolipoprotein E-deficient (apoE−/− ) mice have been clearly described. In this genetically modified strain, oxidative stress contributes with atherosclerotic lesion progression. However, there are controversial criteria on the vulnerability of female apoE−/− mouse to oxidative stress and atherosclerosis during the fertile period. Thus, the aim of the present work was to examine the implication of vascular oxidative stress during early atherosclerosis development in young apoE−/− female mice. Methods: Fifteen 4-week-old and 24-week-old female apoE−/− mice were fed with a high fat high cholesterol and compared with age-matched wild-type C57BL/6J female mice fed with standard diet. Aortic histopathology, serum lipid profile and redox biomarkers were performed for evaluation. Results: Hematoxylin/eosin staining demonstrated the presence of early atherosclerotic lesions in the apoE−/− mice, which progressed with age. Dihydroethidium staining of aortic sections revealed a significant increase of superoxide anion generation in apoE−/− compared with the wild type mice. The increment of this reactive oxygen species was associated, at least, with the overexpression of Nox2 mRNA levels. In addition, the 8-weekold apoE−/− mice had a significant increment of lipid and protein damage, as well as a disruption of superoxide dismutase and catalase activity, together with a deprivation of reduced glutathione and an impairment of nitric oxide availability. Conclusion: The present study shows that early atherosclerotic lesion formation in young apoE−/− female mice is associated with an increment of Nox2-mediated reactive oxygen species generation with the subsequent redox disruption, suggesting a key role of oxidative stress during atherogenesis in fertile apoE−/− female mice.

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