Deficiency of cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1 accelerates atherogenesis in apolipoprotein E-deficient mice.

Cyclin-dependent kinase inhibitors, p21(Cip1) and p27(Kip1), are upregulated during vascular cell proliferation and negatively regulate growth of vascular cells. We hypothesized that absence of either p21(Cip1) or p27(Kip1) in apolipoprotein E (apoE)-deficiency may increase atherosclerotic plaque formation. Compared to apoE(-/-) aortae, both apoE(-/-)/p21(-/-) and apoE(-/-)/p27(-/-) aortae exhibited significantly more atherosclerotic plaque following a high-cholesterol regimen. This increase was particularly observed in the abdominal aortic regions. Deficiency of p27(Kip1) accelerated plaque formation significantly more than p21(-/-) in apoE(-/-) mice. This increased plaque formation was in parallel with increased intima/media area ratios. Deficiency of p21(Cip1) and p27(Kip1) accelerates atherogenesis in apoE(-/-) mice. These findings have significant implications for our understanding of the molecular basis of atherosclerosis associated with excessive proliferation of vascular cells.