The absence of macrophage Nrf2 promotes early atherogenesis
Abstract
AIMS: The loss of nuclear factor E2-related factor 2 (Nrf2) has been shown to protect against atherogenesis in apoE-deficient mice. The mechanism by which Nrf2 deficiency affords atheroprotection in this model is currently unknown, but combined systemic and local vascular effects on lesion macrophages have been proposed. We investigated the effect of bone marrow-specific loss of Nrf2 on early atherogenesis in low-density lipoprotein (LDL) receptor-deficient (LDLR(-/-)) mice, and assessed the effect of Nrf2 on cellular accumulation of modified LDLs and the expression of inflammatory markers in macrophages. METHODS AND RESULTS: The effect of bone marrow-specific loss of Nrf2 on atherogenesis was studied using bone marrow transplantation of wild-type (WT) or Nrf2(-/-) bone marrow to LDLR(-/-) mice. Mice transplanted with Nrf2(-/-) bone marrow and fed a high-fat diet for 6 weeks exhibited significantly larger atherosclerotic lesions than WT bone marrow transplanted mice. Moreover, in thioglycollate-elicited Nrf2(-/-) macrophages, the uptake of acetylated and malondialdehyde-modified LDLs was increased in comparison with WT controls, with the concomitant increase in the expression of scavenger receptor A and toll-like receptor 4. In addition, the expression of pro-inflammatory monocyte chemoattractant protein-1 and interleukin-6 were increased in Nrf2(-/-) vs. WT macrophages. CONCLUSION: Nrf2 deficiency specific to bone marrow-derived cells aggravates atherosclerosis in LDLR(-/-) mice. Furthermore, the loss of Nrf2 in macrophages enhances foam cell formation and promotes the pro-inflammatory phenotype.
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Lack of Nrf2 promotes aggravation of vessel lesions towards atherosclerosis.
“lack of Nrf2 promotes aggravation of vessel lesions towards atherosclerosis [145].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [145]
Oxidative stress may play a role in the development of vascular complications that promote cardiovascular disease by contributing to the pathogenesis of hypertension and atherosclerosis.
“Oxidative stress may play a role in the development of vascular complications that promote cardiovascular disease by contributing to the pathogenesis of hypertension [143,144] and atherosclerosis [145].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [145]
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Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease
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- Authors
- Ruotsalainen, A.-K., Inkala, M., Partanen, M. E., Lappalainen, J. P., Kansanen, E., Mäkinen, P. I., Heinonen, S. E., Laitinen, H. M., Heikkilä, J., Vatanen, T., Hörkkö, S., Yamamoto, M., Ylä-Herttuala, S., Jauhiainen, M., & Levonen, A.-L.
- Affiliations
- University of Eastern Finland (FI)
- Kuopio University Hospital (FI)
- Oulu University Hospital (FI)
- Tohoku University (JP)
- Finnish Institute for Health and Welfare (FI)
- Corresponding author
- Levonen, Anna-Liisa
- ORCID
- Venue
- Cardiovascular Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-01-22
- Volume
- 98
- Issue
- 1
- Pages
- 107-115
- ISSN
- 0008-6363 (ISSN-L)
- 1755-3245
- OpenAlex
- W1979718416
- Cited by
- 109
- References
- 39
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 8 · 2023: 10 · 2022: 14 · 2021: 8 · 2020: 10 · 2019: 7 · 2018: 8 · 2017: 11 · 2016: 2 · 2015: 6 · 2014: 6 · 2013: 6
- FWCI
- 3.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cardiovascular Research (publishedVersion)
- PubMed (publishedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Funders
- Academy of Finland
- Japan Society for the Promotion of Science (24249015)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Keywords
- Nrf2, atherogenesis, LDL receptor-deficient mice, foam cell formation, macrophage inflammation, scavenger receptor A, TLR4, MCP-1, interleukin-6, high-fat diet, atherosclerosis
- MeSH terms
- Animals, Cholesterol, Female, Macrophages, Mice, Inbred C57BL, Receptors, LDL, Chemokine CCL2, Atherosclerosis, Receptors, Scavenger, NF-E2-Related Factor 2, Mice
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