on February 5, 2004
Published online before print February 5, 2004, doi: 10.1161/01.ATV.0000120373.95552.aa
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Submitted on December 2, 2003
Accepted on January 22, 2004
Oxidized Low-Density Lipoprotein Retards the Growth of Proliferating Cells by Inhibiting Nuclear Translocation of Cell Cycle Proteins
Marjorie E. Zettler ;
From the Cell Biology Laboratory, Division of Stroke and Vascular Disease, St Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada; the Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada; and the Department of Microbiology (G.Z.), University of Texas Health Science Center at San Antonio, TX.
* To whom correspondence should be addressed. E-mail: gpierce{at}sbrc.ca.
Objective--Our study tested the hypothesis that the mitogenic effect of oxidized low-density lipoprotein (oxLDL) on vascular cells may be further enhanced by the presence of cytokines and growth factors known to be present in the atherosclerotic environment.
Methods and Results--Quiescent fibroblasts and vascular smooth muscle cells were treated with 10 or 50 µg/mL minimally-oxidized LDL in combination with serum for 24 or 48 hours. Surprisingly, these cells showed inhibited release from growth arrest and a significant reduction in the number of cells completing the cell cycle when compared with cells treated with serum alone. This was not due to an induction of apoptosis. The antiproliferative effects were not closely associated with changes in the expression of cell cycle proteins. Instead, oxLDL inhibited the translocation of cell cycle proteins Cdc 2, cyclin-dependent kinase (Cdk) 2, Cdk 4, Cyclin A, Cyclin B1, Cyclin D1, and proliferative cell nuclear antigen (PCNA) into the nucleus, as compared with separate treatments with serum alone. Kinase activation associated with specific cell cycle proteins was also inhibited by oxLDL.
Conclusions--oxLDL, in the presence of serum, has a surprising inhibitory effect on cell proliferation that occurs through an inhibition of import of cell cycle proteins into the cell nucleus.
Key words: atherosclerosis • cyclin • kinase, cyclin-dependent • cell proliferation
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