Cdkn2a Is an Atherosclerosis Modifier Locus That Regulates Monocyte/Macrophage Proliferation

Abstract

Objective Common genetic variants in a 58-kilobase region of chr 9p21, near the CDKN2A/CDKN2B tumor suppressor locus, are strongly associated with coronary artery disease. However, the underlying mechanism of action remains unknown. Methods and Results We previously reported a congenic mouse model harboring an atherosclerosis susceptibility locus and the region of homology with the human 9p21 locus. Microarray and transcript-specific expression analyses showed markedly decreased Cdkn2a expression, including both p16INK4a and p19ARF, but not Cdkn2b (p15INK4b), in macrophages derived from congenic mice compared to controls. Atherosclerosis studies in subcongenic strains revealed genetic complexity and narrowed one locus to a small interval including Cdkn2a/b. Bone marrow (BM) transplantation studies implicated myeloid lineage cells as the culprit cell type rather than resident vascular cells. To directly test the role of BM-derived Cdkn2a transcripts in atherogenesis and inflammatory cell proliferation, we performed a transplantation study utilizing Cdkn2a+/− cells in the Ldlr−/− mouse model. Cdkn2a-deficient BM recipients exhibited accelerated atherosclerosis, increased Ly6Chi pro-inflammatory monocytes and increased monocyte/macrophage proliferation compared to controls. Conclusions These data provide a plausible mechanism for accelerated atherogenesis in susceptible congenic mice, involving decreased expression of Cdkn2a and increased proliferation of monocyte/macrophages, with possible relevance to the 9p21 human locus.

Cyclin-dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis

“…We recently reported that CDKN2B does play a role in vascular SMC physiology and that Cdkn2b knockout mice develop advanced aneurysms related to accelerated SMC apoptosis and medial thinning (16). Because the mechanism(s) by which 9p21 promote coronary disease remain unclear and the subject of debate (17)(18)(19)(20)(21)(22), we hypothesized that CDKN2B's effects on programmed cell death contribute to the development of CAD by stimulating the accumulation of necrotic debris within the evolving plaque. In the experiments discussed below, we continued to pursue the role of this candidate gene in a murine model of atherogenesis, with a focus on its ability to regulate the clearance of apoptotic bodies (ABs) and the proatherosclerotic consequences of failed phagocytosis.…”

Gene Expression Profiling Reveals Distinct Molecular Signatures Associated With the Rupture of Intracranial Aneurysm

“…mice, and decreased expression of Cdkn2a led to inflammatory monocyte/macrophage proliferation in the circulation. 41 We also identified increased expressions of several histone genes (Figure 3), which reflected the over-representation of genes related to nucleosome in the upregulated genes (Table 2), indicating increased cell proliferation in RIAs. In the previous study, we showed the association of the 9p21 risk allele was somewhat stronger for RIAs than for UIAs.…”

Molecular Biology of Atherosclerosis

“…Only bone-marrow derived cells with the CDKN2A deficiency affected atherosclerosis. Mice heterozygous for the defective gene showed an increase in the proportion of classically activated, circulating monocytes (Ly6C hi ) as well as increased proliferation of activated macrophages (962). How these and other results in mice (see …”

“…Reverse BMT showed that arterial wall expression of INK4a and ARF did not affect atherosclerosis (962). Another study found decreased lesion size with CDKN2A KO but no effect of heterozygosity in apo*E Leiden mice.…”