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.

MicroRNA Regulation of Vascular Smooth Muscle Function and Phenotype

“…5 Although it is tempting to conceptualize the VSMC as existing in only 1 of 2 dichotomous states (ie, either a synthetic or contractile state), it is important to note that these changes occur on a spectrum and that in addition to re-entering the cell-cycle, the dedifferentiated VSMC can also activate programmed cell death pathways 6,7 and elaborate proinflammatory cytokines. 8 Furthermore, the activated VSMC can go to date as to assume behaviors typically ascribed only to other cell types, including phagocytosis and efferocytosis, 9 ossification, 10 reverse cholesterol transport, 9,11 and even foam cell formation. 12,13 Indeed, one of the more exciting recent findings made possible by the use of elegant in vivo lineage tracing systems suggests that the VSMC can assume a macrophagelike phenotype in the developing atherosclerotic plaque, thus challenging the paradigm that lesional foam cells arise predominantly from bone marrow-derived monocytes.…”

Human Genetics of Atherothrombotic Disease and its Risk Factors

“…The same authors then went on to show that Cdnk2b-deficient mice developed increased atherosclerosis with advanced plaques and large necrotic cores accompanied by impaired efferocytosis of apoptotic bodies by macrophages, increased foam cell formation, and increased inflammatory responses. 4 Although much work remains to be done, these findings implicate CDKN2B as potentially causally involved vascular diseases associated with genetic variation at C9CAR, suggesting that regulation of vascular smooth muscle cell apoptosis may be an important mediator, and also implicate the potential for p53 involvement in vascular disease.…”

CDKN2A and CDKN2B methylation in coronary heart disease cases and controls

“…CDKN2B has been previously detected as a candidate gene in CHD (19)(20)(21). Kojima et al (22) demonstrated that loss of CDKN2B promoted advanced development of atherosclerotic plaques, which suggests a crucial role for CDKN2B in the initiation and development of CHD. An inverse correlation between CDKN2B hypermethylation and low expression has previously been found in CHD (23).…”