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Cited by 83Atherosclerosis and Cardiovascular DiseasesCholesterol and Lipid MetabolismPhagocytosis and Immune Regulation

Low-Density Lipoprotein Receptor–Related Protein 1 Prevents Early Atherosclerosis by Limiting Lesional Apoptosis and Inflammatory Ly-6C high Monocytosis: Evidence That the Effects Are Not Apolipoprotein E Dependent

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Yancey, Patricia G., Ding, Yu, Fan, Daping, Blakemore, John L., Zhang, Youmin, Ding, Lei, Zhang, Jiabao, Linton, MacRae F. +1 more·2011·Circulation
DOI 10.1161/circulationaha.111.032268PMC PMC3144781
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Abstract

Background—: We previously demonstrated that macrophage low-density lipoprotein receptor (LDLR)–related protein 1 (LRP1) deficiency increases atherosclerosis despite antiatherogenic changes including decreased uptake of remnants and increased secretion of apolipoprotein E (apoE). Thus, our objective was to determine whether the atheroprotective effects of LRP1 require interaction with apoE, one of its ligands with multiple beneficial effects. Methods and Results—: We examined atherosclerosis development in mice with specific deletion of macrophage LRP1 (apoE −/− MΦLRP1 −/− ) and in LDLR −/− mice reconstituted with apoE −/− MΦLRP1 −/− bone marrow. The combined absence of apoE and LRP1 promoted atherogenesis more than did macrophage apoE deletion alone in both apoE-producing LDLR −/− mice (+88%) and apoE −/− mice (+163%). The lesions of both mouse models with apoE −/− LRP1 −/− macrophages had increased macrophage content. In vitro, apoE and LRP1 additively inhibit macrophage apoptosis. Furthermore, there was excessive accumulation of apoptotic cells in lesions of both LDLR −/− mice (+110%) and apoE −/− MΦLRP1 −/− mice (+252%). The apoptotic cell accumulation was partially due to decreased efferocytosis as the ratio of free to cell-associated apoptotic nuclei was 3.5-fold higher in lesions of apoE −/− MΦLRP1 −/− versus apoE −/− mice. Lesion necrosis was also increased (6 fold) in apoE −/− MΦLRP1 −/− versus apoE −/− mice. Compared with apoE −/− mice, the spleens of apoE −/− MΦLRP1 −/− mice contained 1.6- and 2.4-fold more total and Ly6-C high monocytes. Finally, there were 3.6- and 2.4-fold increases in Ly6-C high and CC-chemokine receptor 2–positive cells in lesions of apoE −/− MΦLRP1 −/− versus apoE −/− mice, suggesting that accumulation of apoptotic cells enhances lesion development and macrophage content by promoting the recruitment of inflammatory monocytes. Conclusion—: Low-density lipoprotein receptor protein 1 exerts antiatherogenic effects via pathways independent of apoE involving macrophage apoptosis and monocyte recruitment.

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Authors
Yancey, P. G., Ding, Y., Fan, D., Blakemore, J. L., Zhang, Y., Ding, L., Zhang, J., Linton, M. F., & Fazio, S.
Affiliations
Jilin University (CN)
ORCID
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2011-07-26
Volume
124
Issue
4
Pages
454-464
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/circulationaha.111.032268
PMC
PMC3144781
OpenAlex
W2571754620
Cited by
83
References
50
Citations by year
2026: 3 · 2025: 5 · 2024: 4 · 2023: 3 · 2022: 8 · 2021: 8 · 2020: 3 · 2019: 8 · 2018: 6 · 2017: 5 · 2016: 4 · 2015: 8 · 2014: 4 · 2013: 6 · 2012: 8
FWCI
2.55
Type
journal article
Language
en
Open access
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL057986, HL57986, R01HL086988, HL086988)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK59637, U24DK059637)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords
LRP1, macrophages, atherosclerosis, apolipoprotein E, macrophage apoptosis, efferocytosis, Ly6Chi monocytes, CCR2, atherosclerotic plaque, Ldlr knockout mice, bone marrow reconstitution, atheroprotection
MeSH terms
Animals, Antigens, Ly, Apolipoproteins E, Female, Leukocyte Disorders, Macrophages, Mice, Inbred C57BL, Monocytes, Receptors, LDL, Spleen, Bone Marrow Transplantation, Apoptosis, Mice, Knockout, Tumor Suppressor Proteins, Low Density Lipoprotein Receptor-Related Protein-1, Atherosclerosis, Mice

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