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

Thomas E. Sussan, Jonathan Jun, Rajesh Thimmulappa, Djahida Bedja, Maria Antero, Kathleen L Gabrielson, Vsevolod Polotsky, Shyam Biswal

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article numbere3791
JournalPLoS One
Volume3
Issue number11
DOIs
StatePublished - Nov 21 2008

Fingerprint

Apolipoproteins E
atherosclerosis
Atherosclerosis
Antioxidants
antioxidant activity
mice
Oxidative stress
Macrophages
Oxidative Stress
oxidative stress
Scavenger Receptors
macrophages
pulmonary emphysema
inflammation
Atherogenic Diet
Inflammation
Nutrition
Pulmonary Emphysema
LDL Lipoproteins
asthma

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Disruption of Nrf2, a key inducer of antioxidant defenses, attenuates ApoE-mediated atherosclerosis in mice. / Sussan, Thomas E.; Jun, Jonathan; Thimmulappa, Rajesh; Bedja, Djahida; Antero, Maria; Gabrielson, Kathleen L; Polotsky, Vsevolod; Biswal, Shyam.

In: PLoS One, Vol. 3, No. 11, e3791, 21.11.2008.

Research output: Contribution to journalArticle

@article{641cf8353303417288386bc1f1fdf0db,
title = "Disruption of Nrf2, a key inducer of antioxidant defenses, attenuates ApoE-mediated atherosclerosis in mice",
abstract = "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.",
author = "Sussan, {Thomas E.} and Jonathan Jun and Rajesh Thimmulappa and Djahida Bedja and Maria Antero and Gabrielson, {Kathleen L} and Vsevolod Polotsky and Shyam Biswal",
year = "2008",
month = "11",
day = "21",
doi = "10.1371/journal.pone.0003791",
language = "English (US)",
volume = "3",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "11",

}

TY - JOUR

T1 - Disruption of Nrf2, a key inducer of antioxidant defenses, attenuates ApoE-mediated atherosclerosis in mice

AU - Sussan, Thomas E.

AU - Jun, Jonathan

AU - Thimmulappa, Rajesh

AU - Bedja, Djahida

AU - Antero, Maria

AU - Gabrielson, Kathleen L

AU - Polotsky, Vsevolod

AU - Biswal, Shyam

PY - 2008/11/21

Y1 - 2008/11/21

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=56849124834&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=56849124834&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0003791

DO - 10.1371/journal.pone.0003791

M3 - Article

VL - 3

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 11

M1 - e3791

ER -