The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.
Mertk Receptor Mutation Reduces Efferocytosis Efficiency and Promotes Apoptotic Cell Accumulation and Plaque Necrosis in Atherosclerotic Lesions of Apoe −/− Mice
Open accessAbstract
Objective— Atherosclerotic plaques that are prone to disruption and acute thrombotic vascular events are characterized by large necrotic cores. Necrotic cores result from the combination of macrophage apoptosis and defective phagocytic clearance (efferocytosis) of these apoptotic cells. We previously showed that macrophages with tyrosine kinase-defective Mertk receptor (Mertk KD ) have a defect in phagocytic clearance of apoptotic macrophages in vitro. Herein we test the hypothesis that the Mertk KD mutation would result in increased accumulation of apoptotic cells and promote necrotic core expansion in a mouse model of advanced atherosclerosis. Methods and Results— Mertk KD ; Apoe −/− mice and control Apoe −/− mice were fed a Western-type diet for 10 or 16 weeks, and aortic root lesions were analyzed for apoptosis and plaque necrosis. We found that the plaques of the Mertk KD ; Apoe −/− mice had a significant increase in terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive apoptotic cells. Most importantly, there were more non-macrophage-associated apoptotic cells in the Mertk KD lesions, consistent with defective efferocytosis. The more advanced (16-week) Mertk KD ; Apoe −/− plaques were more necrotic, consistent with a progression from apoptotic cell accumulation to plaque necrosis in the setting of a defective efferocytosis receptor. Conclusion— In a mouse model of advanced atherosclerosis, mutation of the phagocytic Mertk receptor promotes the accumulation of apoptotic cells and the formation of necrotic plaques. These data are consistent with the notion that a defect in an efferocytosis receptor can accelerate the progression of atherosclerosis and suggest a novel therapeutic target to prevent advanced plaque progression and its clinical consequences.
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In the citing paper
“Conversely, mice lacking MERTK or expressing a constitutively inactive form of MERTK show larger plaque size and increased necrotic core area compared with control mice196,197.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [196]
In the citing paper
“The impaired ability of macrophage efferocytosis would enhance atherogenesis [139,140,141] and atherosclerotic plaque instability [142,143,144].”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [143]
Citations
Cites
Inflammation in atherosclerosis
Libby, P. (2002) · Nature · doi:10.1038/nature01323 · Cited by 8,315
Inflammation in Atherosclerosis
Libby, P. (2012) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.108.179705 · Cited by 3,796
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Self-citationPhagocytosis and clearance of apoptotic cells is mediated by MER
Scott, R. S., McMahon, E. J., Pop, S. M., Reap, E. A., Caricchio, R., Cohen, P. L., Earp, H. S., & Matsushima, G. K. (2001) · Nature · doi:10.1038/35075603 · Cited by 1,215
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Consequences and Therapeutic Implications of Macrophage Apoptosis in Atherosclerosis
Tabas, I. A. (2005) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000184783.04864.9f · Cited by 641
Self-citationCohen, P. L., Caricchio, R., Abraham, V., Camenisch, T. D., Jennette, J. C., Roubey, R. A. S., Earp, H. S., Matsushima, G. K., & Reap, E. A. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20012094 · Cited by 637
Consequences of cellular cholesterol accumulation: basic concepts and physiological implications
Tabas, I. A. (2002) · Journal of Clinical Investigation · doi:10.1172/jci16452 · Cited by 608
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Macrophages in atherosclerosis: a dynamic balance
Moore, K. J., Sheedy, F. J., & Fisher, E. A. (2013) · Nature reviews. Immunology · doi:10.1038/nri3520 · Cited by 2,559
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
Inflammation 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
Self-citationApoptotic cell clearance: basic biology and therapeutic potential
Poon, I. K. H., Lucas, C. D., Rossi, A. G., & Ravichandran, K. S. (2014) · Nature Reviews Immunology · doi:10.1038/nri3607 · Cited by 1,223
Macrophage death and defective inflammation resolution in atherosclerosis
Tabas, I. (2010) · Nature Reviews Immunology · doi:10.1038/nri2675 · Cited by 1,120
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Metadata
- Authors
- Thorp, E., Cui, D., Schrijvers, D. M., Kuriakose, G., & Tabas, I.
- Affiliations
- Columbia University (US)
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2008-08
- Volume
- 28
- Issue
- 8
- Pages
- 1421-1428
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- PMC
- PMC2575060
- OpenAlex
- W2122693935
- Cited by
- 357
- References
- 38
- Citations by year
- 2026: 22 · 2025: 16 · 2024: 25 · 2023: 13 · 2022: 19 · 2021: 21 · 2020: 24 · 2019: 22 · 2018: 25 · 2017: 26 · 2016: 22 · 2015: 19 · 2014: 19 · 2013: 23 · 2012: 19
- FWCI
- 5.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL-75662, P01HL054591, R01HL075662, HL 54591)
- 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
- efferocytosis, macrophage apoptosis, ApoE-deficient mice, plaque progression, Western diet, aortic root lesions, therapeutic target
- MeSH terms
- c-Mer Tyrosine Kinase, Animals, Aorta, Apolipoproteins E, Disease Models, Animal, Foam Cells, Male, Mutation, Phagocytosis, Proto-Oncogene Proteins, Apoptosis, Mice, Knockout, In Situ Nick-End Labeling, Receptor Protein-Tyrosine Kinases, Atherosclerosis, Mice
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