The growth suppressor p27(Kip1) protects against diet-induced atherosclerosis

The molecular basis of atherosclerosis is associated with excessive prolife ration of vascular cells. Previous studies have suggested an inverse correl ation between the expression of the growth suppressor p27(Kip1) (p27) and c ellular proliferation within human atherosclerotic tissue. However, no caus al link between diminished p27 expression and atherogenesis has been establ ished. We investigated the effect of p27 inactivation on diet-induced ather ogenesis. We find that p27-deficient mice challenged with a high-fat diet f or 1 month remain normocholesterolemic and have essentially no visible athe romas. However, when generated in an apolipoprotein E-null genetic backgrou nd that leads to severe hypercholesterolemia in response to the atherogenic diet, deletion of p27 enhances arterial cell proliferation (similar to fou rfold) and accelerates atherogenesis (similar to sixfold) compared with apo lipoprotein E-deficient mice with an intact p27 gene. Analysis of apolipopr otein E-null mice bearing only one p27 allele inactivated reveals that a mo derate decrease in p27 protein expression in the setting of hypercholestero lemia is sufficient to predispose to atherogenesis. Thus, our study establi shes a molecular link between decreased p27 protein expression and atheroge nesis in hypercholesterolemic animals.