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.
Akyürek
Levent M
LM
National Human Genome Research Institute and National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Boehm
Manfred
M
Olive
Michelle
M
Zhou
Alex-Xianghua
AX
San
Hong
H
Nabel
Elizabeth G
EG
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002784:Cholesterol / Q000008:administration & dosage; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000172:deficiency*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis / Q000172:deficiency*; D004036:Diet, Atherogenic; D051379:Mice; D008817:Mice, Mutant Strains
D001057:Apolipoproteins E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D002784:Cholesterol