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Oxidized LDL Induces Proliferation and Hypertrophy in Human Umbilical Vein Endothelial Cells via Regulation of p27^Kip1 Expression: Role of RhoA

Stefan Seibold^*, Dorothea Schürle^*, Alexandra Heinloth^*, Gunter Wolf, Martin Wagner^* and Jan Galle^*

*Department of Medicine, Division of Nephrology, University Hospital, Würzburg, Germany; and Department of Medicine, Division of Nephrology, University Hospital, Hamburg, Germany

Correspondence to Prof. Dr. Jan Galle, Department of Medicine, University Hospital Würzburg, Joseph-Schneider-Strasse 2, D-97080 Würzburg, Germany. Phone: +49-931-201-36194; Fax: +49-931-201-36502; E-mail: J-C.Galle{at}mail.uni-wuerzburg.de

Oxidized LDL (OxLDL) induces proliferation in human umbilical vein endothelial cells (HUVEC). The influence of OxLDL on the cyclin-dependent kinase inhibitor p27^Kip1, on the activity of the small GTPase RhoA as a known regulator of p27^Kip1, and on resulting cell proliferation and hypertrophy was studied. HUVEC were stimulated with OxLDL (1 to 50 µg/ml). Proliferation was quantified by ³H-thymidine incorporation, colorimetric 3-(4,5-dimethyl-2-thiazyl)-2,5-diphenyl-2h-tetrazolium bromide assay, and cell count and was compared with proliferation of HUVEC that were transfected with dominant negative RhoA or treated with the Rho-kinase inhibitor Y27632. Hypertrophy was quantified by ³H-leucine incorporation and by planimetry. p27^Kip1 expression was determined by Western blot analysis. p27^Kip1 was downregulated by transient transfection with antisense oligonucleotides. Low concentrations of OxLDL induced proliferation of HUVEC, paralleled by a persistent decrease of p27^Kip1 expression. With the use of antisense oligonucleotides, further downregulation of p27^Kip1 expression enhanced the OxLDL-induced proliferative response. High concentrations of OxLDL resulted in cellular hypertrophy and caused a delayed increase in p27^Kip1 expression after initial downregulation. Concomitant, OxLDL caused a significant activation of the small GTPase RhoA. In cells that were transfected with dominant negative RhoA, the effect of OxLDL on p27^Kip1 expression and on cellular proliferation was abolished. HUVEC that were preincubated with the Rho-kinase inhibitor Y27632 also showed a significantly decreased proliferative response to OxLDL stimulation. In summary, OxLDL has a dual effect on cell-cycle progression via regulation of p27^Kip1 expression, resulting in cellular proliferation and hypertrophy, involving activation of RhoA. OxLDL may importantly contribute to vascular hyperplasia in atherosclerosis and other diseases associated with increased levels of OxLDL.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673