Deletion of Macrophage LDL Receptor–Related Protein Increases Atherogenesis in the Mouse
Abstract
Macrophage low-density lipoprotein receptor–related protein (LRP) mediates internalization of remnant lipoproteins, and it is generally thought that blocking lipoprotein internalization will reduce foam cell formation and atherogenesis. Therefore, our study examined the function of macrophage LRP in atherogenesis. We generated transgenic mice that specifically lack macrophage LRP through Cre/lox recombination. Transplantation of macrophage LRP −/− bone marrow into lethally irradiated female LDLR −/− recipient mice resulted in a 40% increase in atherosclerosis. The difference in atherosclerosis was not caused by altered serum lipoprotein levels. Furthermore, deletion of macrophage LRP decreased uptake of 125 I–very-low-density lipoprotein compared with wild-type cells in vitro. The increase in atherosclerosis was accompanied by increases in monocyte chemoattractant protein type-1, tumor necrosis factor-α, and proximal aorta macrophage cellularity. We also found that deletion of macrophage LRP increases matrix metalloproteinase-9. This increase in matrix metalloproteinase-9 was associated with a higher frequency of breaks in the elastic lamina. Contrary to what was found with other lipoprotein receptors, deletion of LRP increases atherogenesis in hypercholesterolemic mice. Our data support the hypothesis that macrophage LRP modulates atherogenesis through regulation of inflammatory responses.
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The impaired interaction of apoE Sendai with LRP1 may have functional consequences involving lesion inflammation.
“As LRP1 is also involved in macrophage infl ammation and signaling ( 16, 52, 53 ), the impaired interaction of apoE Sendai with LRP1 may also have functional consequences involving lesion infl ammation.”
From Macrophage-derived apoESendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic mice (2014) · cites this paper as [53]
Loss of LRP1 in haematopoietic cells increases atherosclerotic lesion area and necrotic core size in athero-prone mice fed a high-fat diet.
“Consistent with the role of defective efferocytosis in contributing to atherosclerosis progression, loss of LRP1 in haematopoietic cells increases atherosclerotic lesion area and necrotic core size in athero-prone mice fed a high-fat diet199,200.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [200]
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Self-citation
- Authors
- Overton, C. D., Yancey, P. G., Major, A. S., Linton, M. F., & Fazio, S.
- Affiliations
- Vanderbilt University Medical Center (US)
- Venue
- Circulation Research
- Published
- 2007-03-16
- Volume
- 100
- Issue
- 5
- Pages
- 670-677
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W1982962304
- Cited by
- 159
- References
- 55
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 6 · 2023: 10 · 2022: 13 · 2021: 11 · 2020: 8 · 2019: 7 · 2018: 9 · 2017: 12 · 2016: 13 · 2015: 11 · 2014: 10 · 2013: 9 · 2012: 6
- FWCI
- 2.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5f32hl010206-02)
- National Heart, Lung, and Blood Institute (R01HL057986, HL57986, HL010206, HL07721)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK59637)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- LRP, atherogenesis, atherosclerosis, foam cell formation, bone marrow transplantation, macrophage inflammation, MCP-1, TNF-α, MMP-9, hypercholesterolemia, lipoprotein receptors
- MeSH terms
- Animals, Dietary Fats, Female, Mice, Inbred C57BL, Mice, Transgenic, Macrophages, Peritoneal, Mice, Knockout, Inflammation Mediators, Low Density Lipoprotein Receptor-Related Protein-1, Atherosclerosis, Mice
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