Abstract 314: Nrf2 Expression Enhances Atherosclerotic Lesion Formation
Background: Nrf2 has been shown to be an important transcription factor that regulates the expression of phase 2 detoxifying and antioxidant genes. Nrf2 expression in vascular cells appear to be a key factor in the cellular protection against oxidative stress and inflammation. Our hypothesis is that if Nrf2 is indeed an important protective factor in vascular cells, decreased or absent expression would result in enhancement of atherosclerotic lesions.
Methods: To evaluate our hypothesis, we developed Nrf2 KO mice in the apoE null background by sequential breeding, resulting in Nrf2 homozygous KO (Nrf2−/−, apoE−/−), heterozygous KO (Nrf2+/−, apoE−/−) and wild-type (WT) littermates (Nrf2+/+, apoE−/−). Animals were fed a chow diet, bled and euthanized at 14 weeks of age, when aorta and other organs were harvested. Atherosclerotic lesions were scored in the aortic root and expressed as average lesional area mm2/section. Plasma lipoproteins were determined by enzymatic methods. Peritoneal macrophages lipid loading was assessed by the percentage of oil Red O-stained cells after incubation with oxLDL 50–100 μg/ml for 48 hours.
Results: Homozygous KO mice exhibited decreased levels of liver antioxidant genes such as heme oxygenase-1, catalase and NAD(P)H: quinone oxidoreductase resulting in increased tissue oxidative stress as evidenced by greater hepatic MDA levels. Contrary to our hypothesis, homozygous KO males exhibited 47% and 53% lower atherosclerotic lesions as compared to heterozygous KO or WT controls, respectively. Homozygous KO mice also exhibited significantly lower plasma total and non-HDL cholesterol. Peritoneal macrophages from homozygous KO mice displayed lower lipid loading when compared to WT controls (p < 0.005) despite increased reactive oxygen species generation.
Conclusions: Absent Nrf2 expression results in lower atherosclerotic lesion formation, likely due to a combination of systemic metabolic and vascular local effects.