title: Quantification of the cell-cycle inhibitors p27(Kip1) and p21(Cip1) in human atherectomy specimens: primary stenosis versus restenosis.
abstract: Proliferation, a key determinator of vascular proliferative diseases, is dependent on cyclin/cyclin-dependent kinase (CDK) complexes, which are controlled by cyclin-dependent kinase inhibitors (CKIs) such as p27(Kip1) and p21(Cip1). Both have prognostic significance in various human malignancies. We have determined the levels of p27(Kip1) and p21(Cip1) in human directional coronary atherectomy specimens of primary lesions (n = 15) and lesions of in-stent restenosis (n = 18) in comparison to those of other vascular regions and have correlated CKI levels with clinical data. Quantitative immunoblotting demonstrated low expression of p27(Kip1) in primary lesions (5.9 +/- 0.5 ng/mg protein) compared with that in aorta (14.9 +/- 0.9 ng/mg), internal mammary artery (16.7 +/- 1.1 ng/mg), and carotid artery thrombendarterectomy specimens (16.5 +/- 1.7 ng/mg). Similarly, p27(Kip1) levels in lesions of in-stent restenosis were found to be significantly reduced (6.3 +/- 1.1 ng/mg; mean time of restenosis development 367 +/- 61 days). p27(Kip1) levels did, however, not have prognostic significance for the development of restenosis, and expression levels of proliferating cell nuclear antigen and CDK2 were similar in all groups examined, indicating low proliferative activity. Clinically, p27(Kip1) was not of value in predicting the development of restenosis. Furthermore, p27(Kip1) tissue levels were not increased in statin-treated patients, implying that the favorable effect of these drugs is not a result of p27(Kip1) stabilization. However, the relative content of p21(Cip1) was found to be significantly up-regulated in restenosis compared with that in primary lesions (225%) and the other vascular regions. Our data imply that negative-feedback mechanisms are still intact in coronary proliferative disease, thereby contrasting the finding of deregulated proliferation in malignancies.
authors.affiliation: Department of Internal Medicine, Giessen University, the Kerckhoff Klinik, Bad Nauheim, and Zentralklinikum Suhl, Germany. ruediger.braun-dullaeus@innere.med.uni-giessen.de
authors.forename: Ruediger C
authors.initials: RC
authors.lastname: Braun-Dullaeus
authors.forename: Almut
authors.initials: A
authors.lastname: Ziegler
authors.forename: Rainer M
authors.initials: RM
authors.lastname: Bohle
authors.forename: Erwin
authors.initials: E
authors.lastname: Bauer
authors.forename: Stefan
authors.initials: S
authors.lastname: Hein
authors.forename: Harald
authors.initials: H
authors.lastname: Tillmanns
authors.forename: Werner
authors.initials: W
authors.lastname: Haberbosch
mesh_terms: D001011:Aorta / Q000378:metabolism / Q000473:pathology; D017225:Atherectomy, Coronary; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D023903:Coronary Restenosis / Q000378:metabolism* / Q000473:pathology; D023921:Coronary Stenosis / Q000378:metabolism* / Q000473:pathology; D003331:Coronary Vessels / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism*; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D008297:Male; D008323:Mammary Arteries / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27