Abstract
BackgroundOxidative 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.Principal FindingsTo 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.ConclusionsNrf2 is pro-atherogenic in mice, despite its antioxidative function. The net pro-atherogenic effect of Nrf2 may be mediated via positive regulation of CD36. Our data demonstrates that the potential effects of Nrf2-targeted therapies on cardiovascular disease need to be investigated.
Highlights
Cardiovascular disease is responsible for 40% of all deaths in the US and remains a global public health problem [1]
Nuclear factor E2-related factor 2 (Nrf2) is pro-atherogenic in mice, despite its antioxidative function
The net pro-atherogenic effect of Nrf2 may be mediated via positive regulation of CD36
Summary
Cardiovascular disease is responsible for 40% of all deaths in the US and remains a global public health problem [1]. Atherosclerosis, which is characterized by deposition of fatty plaques in the arterial walls, is a leading cause of cardiovascular disease. Once in the arterial wall, macrophages absorb LDL cholesterol molecules, causing them to develop into foam cells. These cells in turn release chemokines and cytokines, which further enhance inflammatory cell recruitment and perpetuate plaque formation. OxLDL has multiple pro-inflammatory properties, including promotion of monocyte adhesion to the endothelial cell wall and increased expression of pro-inflammatory chemokines [6]. Oxidative stress and inflammation are two critical factors that drive the formation of plaques in atherosclerosis. Our previous studies have shown that disruption of Nrf in mice (Nrf22/2) causes increased susceptibility to pulmonary emphysema, asthma and sepsis due to increased oxidative stress and inflammation. We have tested the hypothesis that disruption of Nrf in mice causes increased atherosclerosis
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