Cited by 168Phagocytosis and Immune RegulationAtherosclerosis and Cardiovascular DiseasesCholesterol and Lipid Metabolism

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Macrophage LRP-1 Controls Plaque Cellularity by Regulating Efferocytosis and Akt Activation

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Yancey, Patricia G., Blakemore, John, Ding, Lei, Fan, Daping, Overton, Cheryl D., Zhang, Youmin, Linton, MacRae F., Fazio, Sergio·2010·Arteriosclerosis, Thrombosis, and Vascular Biology

DOI 10.1161/atvbaha.109.202051PMC PMC2845445

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Abstract

Objective— The balance between apoptosis susceptibility and efferocytosis of macrophages is central to plaque remodeling and inflammation. LRP-1 and its ligand, apolipoprotein E, have been implicated in efferocytosis and apoptosis in some cell types. We investigated the involvement of the macrophage LRP-1/apolipoprotein E axis in controlling plaque apoptosis and efferocytosis. Method and Results— LRP-1 −/− macrophages displayed nearly 2-fold more TUNEL positivity compared to wild-type cells in the presence of DMEM alone or with either lipopolysaccharide or oxidized low-density lipoprotein. The survival kinase, phosphorylated Akt, was barely detectable in LRP-1 −/− cells, causing decreased phosphorylated Bad and increased cleaved caspase-3. Regardless of the apoptotic stimulation and degree of cell death, LRP-1 −/− macrophages displayed enhanced inflammation with increased IL-1β, IL-6, and tumor necrosis factor-α expression. Efferocytosis of apoptotic macrophages was reduced by 60% in LRP-1 −/− vs wild-type macrophages despite increased apolipoprotein E expression by both LRP-1 −/− phagocytes and wild-type apoptotic cells. Compared to wild-type macrophage lesions, LRP-1 −/− lesions had 5.7-fold more necrotic core with more dead cells not associated with macrophages. Conclusion— Macrophage LRP-1 deficiency increases cell death and inflammation by impairing phosphorylated Akt activation and efferocytosis. Increased apolipoprotein E expression in LRP-1 −/− macrophages suggests that the LRP-1/apolipoprotein E axis regulates the balance between apoptosis and efferocytosis, thereby preventing necrotic core formation.

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Authors: Yancey, P. G., Blakemore, J., Ding, L., Fan, D., Overton, C. D., Zhang, Y., Linton, M. F., & Fazio, S.
Affiliations: Vanderbilt University Medical Center (US)
ORCID: Yancey, Patricia G.
Ding, Lei
Fan, Daping
Linton, MacRae F.
Fazio, Sergio
Venue: Arteriosclerosis, Thrombosis, and Vascular Biology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2010-04
Volume: 30
Issue: 4
Pages: 787-795
ISSN: 1079-5642 (ISSN-L)
1524-4636
DOI: 10.1161/atvbaha.109.202051
PMC: PMC2845445
OpenAlex: W2108626579
Cited by: 168
References: 59
Citations by year: 2026: 12 · 2025: 13 · 2024: 8 · 2023: 12 · 2022: 15 · 2021: 12 · 2020: 7 · 2019: 9 · 2018: 10 · 2017: 10 · 2016: 8 · 2015: 14 · 2014: 6 · 2013: 8 · 2012: 10
FWCI: 4.25
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Heart, Lung, and Blood Institute (R01HL057986, R01HL065709, HL57986, R01HL086988, HL 53989, R01HL065405, HL 65405, R01HL053989, HL65709)
National Institute of Diabetes and Digestive and Kidney Diseases (DK59637, U24DK059637)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
Keywords: LRP1, apolipoprotein E, efferocytosis, macrophage apoptosis, Akt signaling, atherosclerosis, plaque inflammation, necrotic core, macrophage phagocytosis, oxidized LDL, lipopolysaccharide, caspase-3, Bad phosphorylation
MeSH terms: Animals, Apolipoproteins E, Cell Survival, Cells, Cultured, Enzyme Activation, Female, Inflammation, Lipopolysaccharides, Lipoproteins, LDL, Necrosis, Phagocytosis, Phosphorylation, Receptors, LDL, Tumor Necrosis Factor-alpha, Interleukin-6, Apoptosis, Macrophages, Peritoneal, Mice, Knockout, In Situ Nick-End Labeling, Tumor Suppressor Proteins, Low Density Lipoprotein Receptor-Related Protein-1, Atherosclerosis, Proto-Oncogene Proteins c-akt, Mice, Interleukin-1beta

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Macrophage LRP-1 Controls Plaque Cellularity by Regulating Efferocytosis and Akt Activation

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