The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.
Disruption of Nrf2, a Key Inducer of Antioxidant Defenses, Attenuates ApoE-Mediated Atherosclerosis in Mice
Open accessAbstract
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. PRINCIPAL FINDINGS: 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.
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Cites
Cell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway
Kensler, T. W., Wakabayashi, N., & Biswal, S. (2007) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.46.120604.141046 · Cited by 3,630
Self-citationNrf2 is a critical regulator of the innate immune response and survival during experimental sepsis
Thimmulappa, R. K. (2006) · Journal of Clinical Investigation · doi:10.1172/jci25790 · Cited by 1,028 · cited 1×
“Our previous studies have shown that mice that are deficient in Nrf2 are characterized by high levels of oxidative stress and an inappropriate inflammatory response following exposure to a variety of stressors including chronic cigarette smoke-mediated emphysema [19], allergic asthma [20], and endotoxin and acute peri…”
BackgroundInfluentialSelf-citationDisruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice
Rangasamy, T., Guo, J., Mitzner, W. A., Roman, J., Singh, A., Fryer, A. D., Yamamoto, M., Kensler, T. W., Tuder, R. M., Georas, S. N., et al. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20050538 · Cited by 580
Self-citationLaminar Flow Induction of Antioxidant Response Element-mediated Genes in Endothelial Cells
Chen, X.-L., Varner, S. E., Rao, A. S., Grey, J. Y., Thomas, S., Cook, C. K., Wasserman, M. A., Medford, R. M., Jaiswal, A. K., & Kunsch, C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m203161200 · Cited by 333
Kirk, E. A., Dinauer, M. C., Rosen, H., Chait, A., Heinecke, J. W., & LeBoeuf, R. C. (2000) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.20.6.1529 · Cited by 171
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Tebay, L. E., Robertson, H., Durant, S. T., Vitale, S. R., Penning, T. M., Dinkova-Kostova, A. T., & Hayes, J. D. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.021 · Cited by 837
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Metadata
- Authors
- Sussan, T. E., Jun, J., Thimmulappa, R., Bedja, D., Antero, M., Gabrielson, K. L., Polotsky, V. Y., & Biswal, S.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2008-11-21
- Volume
- 3
- Issue
- 11
- Pages
- e3791
- ISSN
- 1932-6203 (ISSN-L)
- OpenAlex
- W1986377088
- Cited by
- 179
- References
- 6
- FWCI
- 2.91
- Type
- journal article
- Language
- en
- Open access
- gold
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- The paper
- Sussan, T. E., Jun, J., Thimmulappa, R., Bedja, D., Antero, M., Gabrielson, K. L., Polotsky, V. Y., & Biswal, S. (2008). Disruption of Nrf2, a Key Inducer of Antioxidant Defenses, Attenuates ApoE-Mediated Atherosclerosis in Mice. PLoS ONE. https://doi.org/10.1371/journal.pone.0003791
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