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.