Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2001; 85(04): 730-735
DOI: 10.1055/s-0037-1615660

Review Articles

Schattauer GmbH

High Density Lipoproteins Induce Cell Cycle Entry in Vascular Smooth Muscle Cells Via Mitogen Activated Protein Kinase-dependent Pathway

Jerzy-Roch Nofer

¹Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität, Münster

²Institut für Arterioskleroseforschung an der Universität Münster, Germany

,

Ralf Junker

¹Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität, Münster

²Institut für Arterioskleroseforschung an der Universität Münster, Germany

,

Ewa Pulawski

²Institut für Arterioskleroseforschung an der Universität Münster, Germany

,

Manfred Fobker

¹Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität, Münster

,

Bodo Levkau

²Institut für Arterioskleroseforschung an der Universität Münster, Germany

,

Arnold von Eckardstein

¹Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität, Münster

²Institut für Arterioskleroseforschung an der Universität Münster, Germany

,

Udo Seedorf

²Institut für Arterioskleroseforschung an der Universität Münster, Germany

,

Gerd Assmann

¹Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität, Münster

²Institut für Arterioskleroseforschung an der Universität Münster, Germany

,

Michael Walter

¹Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität, Münster

²Institut für Arterioskleroseforschung an der Universität Münster, Germany

› Author Affiliations

Summary

In this study we found that HDL acts as a potent and specific mitogen in vascular smooth muscle cells (VSMC) by stimulating entry into S-phase and DNA synthesis in a time- and concentration-dependent manner, induction of cyclins D1, E, and A, as well as activation of cyclin D-dependent kinases as inferred from phosphorylation of the retinoblastoma protein (pRb). Moreover, HDL induced activation of the mitogen-activated protein kinase pathway including Raf-, MEK-1, and ERK1/2, as well as the expression of proto-oncogen c-fos, which is controlled by ERK1/2. PD98059, an inhibitor of MEK-1 blocked the mitogenic activity of HDL and cyclin D1 expression. HDL-induced VSMC proliferation, cell cycle progression, cyclin D1 expression, and activation of the Raf-1/MEK-1/ERK1/2 cascade were blocked by pre-incubation of cells with pertussis toxin indicating involvement of trimeric G-protein. By contrast, none of these responses was inhibited by the protein kinase C inhibitor, GF109203X. The mitogenic effects of native HDL were not mimicked by apo A-I, reconstituted HDL containing apo A-I, or cholesterol-containing liposomes. In conclusion, HDL possesses an intrinsic property to induce G-protein- and MAP-kinase-dependent proliferation and cell cycle progression in VSMC. The strong and specific mitogenic effect of HDL should be taken into account, when therapeutic strategies to elevate the plasma level of these lipoproteins are developed.

Keywords

Keywords

High density lipoproteins - smooth muscle cells - signal transduction - arteriosclerosis

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