on October 9, 2003
Published online before print October 9, 2003, doi: 10.1161/01.ATV.0000100404.05459.39
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Submitted on September 9, 2003
Accepted on September 30, 2003
Apolipoprotein D Inhibits Platelet-Derived Growth Factor-BB-Induced Vascular Smooth Muscle Cell Proliferation by Preventing Translocation of Phosphorylation of Extracellular Signal Regulated Kinase 1/2 to the Nucleus
Jennifer M. Sarjeant ;
From the Cardiovascular Research Program (J.M.S., C.K., S.Y., W.L., H.M., M.R.), The Hospital for Sick Children, and the Departments of Pediatrics, Laboratory Medicine, and Pathobiology and Medicine, University of Toronto; Ottawa Health Research Institute (W.P.), Ottawa Hospital; Division of Anatomical Pathology (E.R.), Ottawa Hospital and Department of Pathology and Laboratory Medicine, University of Ottawa; and Département des Sciences Biologiques (E.R.), Université du Quebec à Montréal, Canada. A.L. and M.R. are presently at the Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif.
* To whom correspondence should be addressed. E-mail: marlener{at}stanford.edu.
Objective--Elevated apolipoprotein D (apoD) levels are associated with reduced proliferation of cancer cells. We therefore investigated whether apoD, which occurs free or associated with HDL, suppresses vascular smooth muscle cell (VSMC) proliferation, which is related to the pathobiology of disease.
Methods and Results--Intense immunoreactivity for apoD was observed in human atherosclerotic plaque but not in normal coronary artery. However, an increase in apoD mRNA was seen in quiescent relative to proliferating fetal lamb aortic VSMCs, and in the rat aortic VSMC line (A10), we demonstrated uptake of apoD from serum. Stable transfection of apoD in A10 cells in the absence of serum did not influence VSMC proliferation assessed by [3H]-thymidine incorporation. ApoD, administered at a dose of 100 ng/mL, completely inhibited basal as well as platelet-derived growth factor (PDGF)-BB-induced VSMC proliferation (P<0.01) but had no effect on fibroblast growth factor-induced VSMC proliferation. ApoD did not suppress PDGF-BB or fibroblast growth factor-2-induced phosphorylation of extracellular signal regulated kinase (ERK) 1/2 but selectively inhibited PDGF-BB-mediated ERK1/2 nuclear translocation.
Conclusions--Our data suggest that apoD selectively modulates the proliferative response of VSMC to growth factors by a mechanisms related to nuclear translocation of ERK1/2.
Key words: apolipoprotein D • vascular smooth muscle cells • platelet-derived growth factor-BB • fibroblast growth factor-2 • extracellular signal-regulated kinase phosphorylation and nuclear translocation • proliferation
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