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.