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Instituto de Biomedicina de Valencia (IBV-CSIC), Spanish Council for Scientific Research, 46010-Valencia, Spain
1Correspondence: Instituto de Biomedicina de Valencia (IBV-CSIC), C/Jaime Roig, 11, 46010 Valencia, Spain. E-mail: vandres{at}ibv.csic.es
The molecular basis of atherosclerosis is associated with excessive
proliferation of vascular cells. Previous studies have suggested an
inverse correlation between the expression of the growth suppressor
p27Kip1 (p27) and cellular proliferation within human
atherosclerotic tissue. However, no causal link between diminished p27
expression and atherogenesis has been established. We investigated the
effect of p27 inactivation on diet-induced atherogenesis. We find that
p27-deficient mice challenged with a high-fat diet for 1 month remain
normocholesterolemic and have essentially no visible atheromas.
However, when generated in an apolipoprotein E-null genetic background
that leads to severe hypercholesterolemia in response to the
atherogenic diet, deletion of p27 enhances arterial cell proliferation
(
fourfold) and accelerates atherogenesis (sixfold) compared with
apolipoprotein E-deficient mice with an intact p27 gene. Analysis of
apolipoprotein E-null mice bearing only one p27 allele
inactivated reveals that a moderate decrease in p27 protein expression
in the setting of hypercholesterolemia is sufficient to predispose to
atherogenesis. Thus, our study establishes a molecular link between
decreased p27 protein expression and atherogenesis in
hypercholesterolemic animals.—Díez-Juan, A., Andrés, V.
The growth suppressor p27Kip1 protects against diet-induced
atherosclerosis.
Key Words: cell cycle • p27 • hypercholesterolemia
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