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J Am Soc Nephrol 11:1819-1825, 2000
© 2000 American Society of Nephrology

Stimulation of NADPH Oxidase by Oxidized Low-Density Lipoprotein Induces Proliferation of Human Vascular Endothelial Cells

ALEXANDRA HEINLOTH, KATHRIN HEERMEIER, ULRIKE RAFF, CHRISTOPH WANNER and JAN GALLE

Department of Medicine, Division of Nephrology, University Hospital of Würzburg, Würzburg, Germany.

Correspondence to Dr. Jan Galle, Department of Medicine, Division of Nephrology, University Hospital of Würzburg, Joseph-Schneider-Straße, 2 D-97080, Würzburg, Germany. Phone: +49 931 201 5331; Fax: +49 931 201 3502; E-mail: j-c.galle{at}mail.uni-wuerzburg.de

Abstract. Oxidized low-density lipoprotein (OxLDL) exerts proliferation and apoptosis in vascular cells, depending on its concentration and the duration of exposure. Recent studies indicate that O2- is involved in cell cycle regulation and that OxLDL stimulates endothelial cells to produce O2-. This study examined the role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase as a potential source for O2- in the proliferation-inducing activity of OxLDL in cultured human umbilical vein endothelial cells (HUVEC). Human LDL was oxidized by Cu++, and proliferation of HUVEC was detected by 3H-thymidine incorporation. OxLDL (5 µg/ml) caused an increase in proliferation of HUVEC of 250 to 300%. OxLDL-induced proliferation was blocked by addition of the antioxidants superoxide dismutase and catalase, suggesting that enhanced O2- formation was involved. Diphenylene iodonium (DPI, 1 µM), an inhibitor of NADPH oxidase, also prevented OxLDL-induced proliferation of HUVEC, indicating that NADPH oxidase was the source for enhanced O2- formation. The OxLDL effect was mimicked by lysophosphatidylcholine (LPC, 10 µM), a compound formed during oxidation of LDL. LPC-induced proliferation was also prevented by coincubation with DPI. Treatment of HUVEC with O2- generated by the xanthine/xanthine oxidase reaction resulted in proliferation as did treatment with OxLDL. As expected, this stimulation could not be blocked by DPI. With the use of the cytochrome c-assay, it was demonstrated that OxLDL and LPC enhanced O2- formation in HUVEC (by factor 3.2 and by factor 3.5, respectively). Supporting the assumption that NADPH oxidase was the enzyme responsible for O2- formation, cells transfected with antisense oligonucleotides for NADPH oxidase showed a significantly reduced O2- formation after stimulation with OxLDL and LPC. OxLDL and its compound LPC induce proliferation of HUVEC through activation of NADPH oxidase. The active NADPH oxidase generates O2-, which mediates the proliferative effects.




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