Oxidative stress and inflammation are two critical factors that drive the formation of plaques in atherosclerosis. Nrf2 is a redox-sensitive transcription factor that upregulates a battery of antioxidative genes and cytoprotective enzymes that constitute the cellular response to oxidative stress. Our previous studies have shown that disruption of Nrf2 in mice ( Nrf2 −/−) causes increased susceptibility to pulmonary emphysema, asthma and sepsis due to increased oxidative stress and inflammation. Here we have tested the hypothesis that disruption of Nrf2 in mice causes increased atherosclerosis.
To investigate the role of Nrf2 in the development of atherosclerosis, we crossed Nrf2 −/− mice with apoliporotein E-deficient ( ApoE −/−) mice. ApoE −/− and ApoE −/− Nrf2 −/− mice were fed an atherogenic diet for 20 weeks, and plaque area was assessed in the aortas. Surprisingly, ApoE −/− Nrf2 −/− mice exhibited significantly smaller plaque area than ApoE −/− controls (11.5% vs 29.5%). This decrease in plaque area observed in ApoE −/− Nrf2 −/− mice was associated with a significant decrease in uptake of modified low density lipoproteins (AcLDL) by isolated macrophages from ApoE −/− Nrf2 −/− mice. Furthermore, atherosclerotic plaques and isolated macrophages from ApoE −/− Nrf2 −/− mice exhibited decreased expression of the scavenger receptor CD36.