Apolipoprotein E Inhibits Platelet-derived Growth Factor-induced Vascular Smooth Muscle Cell Migration and Proliferation by Suppressing Signal Transduction and Preventing Cell Entry to G1 Phase*
- From the Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0529
Abstract
The anti-atherogenic effects of apolipoprotein (apo) E have been attributed to its ability to reduce plasma cholesterol level and to limit foam cell formation. The purpose of this study was to ascertain if apoE also may have cytostatic functions that could attenuate vascular occlusive diseases. Purified apoE inhibited smooth muscle cell migration directed to platelet-derived growth factor (PDGF) or oxidized LDL (oxLDL) (p < 0.0001). The purified apoE also suppressed PDGF- and oxLDL-induced smooth muscle cell proliferation (p < 0.001). These apoE inhibitory effects were not because of suppression of PDGF binding to its receptors on the smooth muscle cells, but was correlated with a significant reduction in agonist-stimulated mitogen-activated protein kinase activity (p < 0.01). ApoE also inhibited PDGF-induced cyclin D1 mRNA expression, suggesting that the apoE effect was mediated by growth arrest at the G0 to G1 phase. Taken together, these results suggest that apoE has cytostatic functions in the vessel wall and may protect against vascular diseases through inhibition of cell signaling events associated with growth factor-induced smooth muscle cell migration and proliferation.
Footnotes
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↵* This research was supported in part by funds from the National Institutes of Health (Grant DK40917) and the Japan Research Foundation for Clinical Pharmacology.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ To whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, 231 Bethesda Ave., Cincinnati, OH 45267-0529. Tel.: 513-558-9152; Fax: 513-558-2141; E-mail: Huidy{at}email.uc.edu.
- Abbreviations:
- apo
-
apolipoprotein
- VLDL
-
very low density lipoproteins
- IDL
-
intermediate density lipoproteins
- LDL
-
low density lipoproteins
- oxLDL
-
oxidized low density lipoproteins
- PDGF
-
platelet-derived growth factor
- PDGF-BB
-
homodimer of PDGF B polypeptide
- MAP kinase
-
mitogen-activated protein kinase
- DMEM
-
Dulbecco’s modified Eagle’s medium
- PHAS-I
-
insulin-regulated phosphorylated heat- and acid-stable protein
- FBS
-
fetal bovine serum
- HPF
-
high power fields
- MTS
-
3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-4-sulfophenyl)-2H-tetrazolium salt
- LRP
-
low density lipoprotein receptor-related protein.
-
- Received March 23, 1998.
- Revision received June 1, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
