The DOI matches its Crossref record; 59 of the 59 references it cites were found in a registry or an index.
Macrophage LRP-1 Controls Plaque Cellularity by Regulating Efferocytosis and Akt Activation
Open accessAbstract
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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“We previously reported that apoE-LRP1 interactions in macrophages control the rate of apoE secretion ( 51 ).”
From Macrophage-derived apoESendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic mice (2014) · cites this paper as [51]
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“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 [199]
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Macrophages in the Pathogenesis of Atherosclerosis
Moore, K. J., & Tabas, I. (2011) · Cell · doi:10.1016/j.cell.2011.04.005 · Cited by 2,669
Borén, J., Chapman, M. J., Krauss, R. M., Packard, C. J., Bentzon, J. F., Binder, C. J., Daemen, M. J., Demer, L. L., Hegele, R. A., Nicholls, S. J., et al. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz962 · Cited by 1,601
Self-citationInflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities
Bäck, M., Yurdagul, A., Tabas, I., Öörni, K., & Kovanen, P. T. (2019) · Nature Reviews Cardiology · doi:10.1038/s41569-019-0169-2 · Cited by 1,341
Efferocytosis in health and disease
Doran, A. C., Yurdagul, A., & Tabas, I. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-019-0240-6 · Cited by 1,066
Phagocytosis of apoptotic cells in homeostasis
Arandjelovic, S., & Ravichandran, K. S. (2015) · Nature Immunology · doi:10.1038/ni.3253 · Cited by 959
Metadata
- 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)
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2010-04
- Volume
- 30
- Issue
- 4
- Pages
- 787-795
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- 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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