Disruption of Nrf2, a key inducer of antioxidant defenses, attenuates ApoE-mediated atherosclerosis in mice.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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. Our data demonstrates that the potential effects of Nrf2-targeted therapies on cardiovascular disease need to be investigated.
Sussan
Thomas E
TE
Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America.
Jun
Jonathan
J
Thimmulappa
Rajesh
R
Bedja
Djahida
D
Antero
Maria
M
Gabrielson
Kathleen L
KL
Polotsky
Vsevolod Y
VY
Biswal
Shyam
S
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D018955:CD36 Antigens / Q000378:metabolism; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress
D000975:Antioxidants; D001057:Apolipoproteins E; D018955:CD36 Antigens; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse