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Cyclin-dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis
Open accessAbstract
Genetic variation at the chromosome 9p21 risk locus promotes cardiovascular disease; however, it is unclear how or which proteins encoded at this locus contribute to disease.We have previously demonstrated that loss of one candidate gene at this locus, cyclin-dependent kinase inhibitor 2B (Cdkn2b), in mice promotes vascular SMC apoptosis and aneurysm progression.Here, we investigated the role of Cdnk2b in atherogenesis and found that in a mouse model of atherosclerosis, deletion of Cdnk2b promoted advanced development of atherosclerotic plaques composed of large necrotic cores.Furthermore, human carriers of the 9p21 risk allele had reduced expression of CDKN2B in atherosclerotic plaques, which was associated with impaired expression of calreticulin, a ligand required for activation of engulfment receptors on phagocytic cells.As a result of decreased calreticulin, CDKN2B-deficient apoptotic bodies were resistant to efferocytosis and not efficiently cleared by neighboring macrophages.These uncleared SMCs elicited a series of proatherogenic juxtacrine responses associated with increased foam cell formation and inflammatory cytokine elaboration.The addition of exogenous calreticulin reversed defects associated with loss of Cdkn2b and normalized engulfment of Cdkn2bdeficient cells.Together, these data suggest that loss of CDKN2B promotes atherosclerosis by increasing the size and complexity of the lipid-laden necrotic core through impaired efferocytosis. Results Cdkn2b regulates atherosclerotic lesion size and features of plaque vulnerability in vivo.To study the effect of Cdkn2b on atherosclerosis in vivo, we evaluated a total of 114 male and female Cdkn2b -/-,ApoE -/-, Cdkn2b +/-,ApoE -/-, and Cdkn2b +/+ ,ApoE -/-mice that had been fed a high-fat Western diet for 4, 8, or 12 weeks.Total atherosclerotic burden was increased in male Cdkn2b -/-,ApoE -/-animals as soon as 8 weeks after initiating the high-fat diet, as measured by the Authorship note: Tom Quertermous and Nicholas J. Leeper contributed equally to this work.
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“cyclin-dependent kinase inhibitor 2B (CDKN2B)-deficient apoptotic cells show decreased expression of calreticulin [149]”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [149]
In the citing paper
“Interestingly, atherosclerotic plaques from patients carrying a genetic variation at the 9p21 locus (which includes the CDKN2B gene), which has been associated with atherosclerosis in humans204,205, have reduced levels of calreticulin compared with atherosclerotic plaques from non-carriers203, further supporting a role for defective efferocytosis in cardiovascular disease206.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [203]
In the citing paper
“For example, Apoe−/− mice with deletion of Cdkn2b had lower levels of calreticulin than control Apoe−/− mice, and Cdkn2b−/−Apoe−/− mice fed a Western diet had increased plaque size and larger necrotic core area than control Apoe−/− mice, which was attributed to intralesional apoptotic cells being resistant to phagocytosis203.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [203]
In the citing paper
“Thus, apoptotic cells without CDKN2B impair macrophages efferocytosis and result in the development of advanced atherosclerotic plaques with large necrotic cores.”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [149]
In the citing paper
“Moreover, supplementation with exogenous calreticulin restores the clearance of CDKN2B-deficient apoptotic cells by macrophages [149].”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [149]
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Metadata
- Authors
- Kojima, Y., Downing, K., Kundu, R., Miller, C., Dewey, F., Lancero, H., Raaz, U., Perisic, L., Hedin, U., Schadt, E., Maegdefessel, L., Quertermous, T., & Leeper, N. J.
- Affiliations
- Stanford Medicine (US)
- Karolinska Institutet (SE)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Leeper, Nicholas J.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2014-02-17
- Volume
- 124
- Issue
- 3
- Pages
- 1083-1097
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3938254
- OpenAlex
- W2110153407
- Cited by
- 148
- References
- 82
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 12 · 2023: 12 · 2022: 11 · 2021: 17 · 2020: 13 · 2019: 14 · 2018: 18 · 2017: 13 · 2016: 15 · 2015: 8 · 2014: 4
- FWCI
- 6.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association (10BGIA3290011)
- Gilead Sciences
- Fondation Leducq
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL103635, K08HL103605, R01HL109512, T32HL007544, T32HL098049, T32HL094274)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Keywords
- CDKN2B, atherosclerosis, efferocytosis, calreticulin, engulfment receptor, macrophage phagocytosis, apoptotic bodies, necrotic core, foam cell formation, vascular smooth muscle cell apoptosis, plaque vulnerability, juxtacrine signaling, inflammatory cytokines, ApoE-deficient mice
- MeSH terms
- Animals, Carotid Arteries, Cells, Cultured, Coronary Vessels, Female, Humans, Macrophages, Male, Mice, Inbred C57BL, Necrosis, Phagocytosis, Down-Regulation, Gene Expression, Retinoblastoma Protein, Apoptosis, Mice, Knockout, Coculture Techniques, Myocytes, Smooth Muscle, Calreticulin, Quantitative Trait Loci, Atherosclerosis, E2F4 Transcription Factor, Cyclin-Dependent Kinase Inhibitor p15, Mice, Plaque, Atherosclerotic
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