© 1997 American Heart Association, Inc.
Articles |
Topographical Association Between the Cyclin-Dependent Kinases Inhibitor P21, p53 Accumulation, and Cellular Proliferation in Human Atherosclerotic Tissue
From the Departments of Pathology (C.I., G.M., E.W., H.E.S.) and Medical Biometrics and Informatics (J.S.M.), University of Freiburg; and the Department of Internal Medicine IV, University of Frankfurt (A.M.Z.), Germany.
Correspondence to Christian Ihling, MD, Department of Pathology, University of Freiburg, Albertstraße 19, D-79104 Freiburg.
Abstract The cell cycle is controlled by
cyclin-dependent protein kinases (CDKs). The activity of these enzymes
is directed by inhibitors of CDKs. The 21-kD protein
product (P21) of the WAF1/CIP1 gene, which can be
transactivated by the protein product of the tumor
suppressor gene p53, acts as an inhibitor of
cyclin-dependent kinases. To assess whether both P21 and p53 may play a
role in the control of cellular proliferation in atherosclerotic
lesions, the topographical association between p53, P21, and the
proliferation marker MIB1/Ki-67, was analyzed by
immunohistochemistry in human carotid atheromatous
plaques of 26 patients. p53 immunoreactivity (IR) was present in 26
of 26 cases in the nuclei of virtually all cell types
(macrophages [MPs], smooth muscle cells [SMCs],
endothelial cells [ECs]) in areas with chronic
inflammation in 71.08±8.28% of the nuclei. p53 staining in the
control tissue from human coronary arteries was present in
0.3±0.45% of the cells (P<.002). P21-IR was present
in 24 of 26 specimens in 64.38±10.13% of the cells (controls:
3.8±1.85%, P<.002) and localized to nuclei of MPs (CD68
positive) and SMCs (
-actin positive), as well as ECs of microvessels
present in 21 specimens (21 of 21) and luminal ECs present in
18 specimens (16 of 18). As shown by double labeling, P21-IR
colocalized with p53-IR in most MPs (24 of 24), intimal SMCs (22 of
24), ECs of microvessels (19 of 21), and luminal ECs (10 of 16).
Interestingly, few p53-positive cells did not show
simultaneous P21-IR, and, conversely, not all P21-positive
cells demonstrated p53-IR. MIB1/Ki-67-positive cells were identified in
21 of 26 tissue specimens in 3.53±1.79% of the nuclei (controls: 0%,
P<.002) and localized principally to MPs bordering the
atheromatous lipid core (21 of 26) and to a few
scattered SMCs (16 of 26), ECs of microvessels (13 of 21), and luminal
ECs (2 of 18). Most importantly, none of the cells coexpressing P21 and
p53 were positive for MIB1/Ki-67-IR, indicating the absence of
proliferating activity. In summary, this study demonstrates that P21-IR
is present in the atherosclerotic plaque and colocalizes with p53
in most MPs, SMCs, and ECs. The lack of proliferation markers in cells
coexpressing p53 and P21 suggests that transcriptional activation of
the WAF1/CIP1 gene by p53 may be involved in the control of
cellular proliferation in advanced human atherosclerotic plaques.
Key Words: cell proliferation • p53 • atherosclerosis • P21 • WAF1/CIP1 gene
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