title: Cyclin-dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis.
abstract: 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 Cdkn2b-deficient 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.
authors: Yoko
authors: Y
authors: Kojima
authors: Kelly
authors: K
authors: Downing
authors: Ramendra
authors: R
authors: Kundu
authors: Clint
authors: C
authors: Miller
authors: Frederick
authors: F
authors: Dewey
authors: Hope
authors: H
authors: Lancero
authors: Uwe
authors: U
authors: Raaz
authors: Ljubica
authors: L
authors: Perisic
authors: Ulf
authors: U
authors: Hedin
authors: Eric
authors: E
authors: Schadt
authors: Lars
authors: L
authors: Maegdefessel
authors: Tom
authors: T
authors: Quertermous
authors: Nicholas J
authors: NJ
authors: Leeper
mesh_terms: D000818:Animals; D017209:Apoptosis; D050197:Atherosclerosis / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D037282:Calreticulin / Q000378:metabolism; D002339:Carotid Arteries / Q000473:pathology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003331:Coronary Vessels / Q000473:pathology; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D050704:E2F4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000201:enzymology; D009336:Necrosis / Q000201:enzymology; D010587:Phagocytosis; D058226:Plaque, Atherosclerotic / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D040641:Quantitative Trait Loci; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D037282:Calreticulin; C493968:Cdkn2b protein, mouse; D050762:Cyclin-Dependent Kinase Inhibitor p15; D050704:E2F4 Transcription Factor; C493763:E2f4 protein, mouse; D016160:Retinoblastoma Protein