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VASCULAR AND HYPERTENSION

Upregulation of Endothelin Receptor B in Human Endothelial Cells by Low-Density Lipoproteins

Gregor Muller^*, Rusan A. Catar^*, Bernd Niemann, Matthias Barton, Lilla Knels, Martina Wendel and Henning Morawietz^*,1

^* Department of Vascular Endothelium and Microcirculation, University of Technology Dresden, D-01307 Dresden, Germany; Institute of Pathophysiology and Department of Cardiothoracic Surgery, Martin Luther University Halle-Wittenberg, D-06097 Halle, Germany; Medical Policlinic, Department of Medicine, University Hospital, CH-8091 Zürich, Switzerland; and Department of Anesthesiology and Intensive Care Medicine, University of Technology Dresden, D-01307 Dresden, Germany

To whom requests for reprints should be addressed at ¹ Department of Vascular Endothelium and Microcirculation, Medical Faculty Carl Gustav Carus, University of Technology Dresden, Fetscherstrasse 74, D-01307 Dresden, Germany. E-mail: Henning.Morawietz{at}tu-dresden.de

Abstract

Low-density lipoproteins (LDLs) represent the most important treatable risk factors for coronary artery disease. Although it has been previously shown that hypercholesterolemia stimulates the endothelin system, the effects of increased levels of LDL on endothelial endothelin receptors have not been previously studied. In particular, the influence of native and oxidatively modified LDLs (nLDLs and oxLDLs) and the regulatory mechanisms in endothelial cells are currently unknown. Human endothelial cells almost exclusively express the endothelin receptor type B (ET_B). Therefore, the effect of nLDL and oxLDL on the expression of ET_B was studied in primary cultures of human umbilical vein endothelial cells (HUVEC). HUVEC were stimulated by nLDL and oxLDL in a time-dependent (1–12 hrs) and dose-dependent (25–100 µg/ml) manner. To analyze signal transduction pathways involved in the regulation of ET_B, protein kinase C (PKC) was inhibited using 100 nM Ro-31-8220. The mRNA expression of ET_B was determined by quantitative reverse transcription–polymerase chain reaction and ET_B protein expression by Western blot. Native LDL induced ET_B mRNA after 1 hr (100 µg/ml, 199 ± 35%, n = 15, P < 0.05 vs. control). Stimulation of HUVEC with oxLDL increased ET_B mRNA expression (1 hr, 100 µg/ml oxLDL: 308 ± 48%, n = 15, P < 0.05 vs. control) as well. Induction of ET_B was also found on the protein level. nLDL was even more potent than oxLDL in inducing ET_B protein expression. Induction of ET_B expression by oxLDL is mediated by PKC. These data demonstrate that low-density lipoproteins even independent of oxidative modification are potent inducers of ET_B receptors at the mRNA and protein level in HUVEC. Given the nitric oxide-releasing capacity of endothelial ET_B receptors, this effect may represent a possible vasoprotective mechanism.

Key Words: endothelin-1 • endothelin receptor B • endothelium • low-density lipoprotein