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

Cyclin-dependent kinase inhibitors, p21Cip1 and p27Kip1, are upregulated during vascular cell proliferation and negatively regulate growth of vascular cells. We hypothesized that absence of either p21Cip1 or p27Kip1 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 p27Kip1 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 p21Cip1 and p27Kip1 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.