Effect of bacterial lipopolysaccharide on endothelin-1 production in human vascular endothelial cells

Background/Aims: The plasma levels of endothelin (ET) are 2–5 fold higher in patients with cirrhosis than in healthy subjects. It has been proposed that endotoxemia could be a mechanism responsible for this phenomenon. However, investigations in rats with cirrhosis indicate that a differential regulation for prepro ET-1 mRNA expression occurs in the liver tissue of these animals but not in the aorta or other organs. The aim of the study was to investigate the effect of bacterial lipopolysaccharide (LPS) on endothelin-1 synthesis and release in cultured human vascular endothelial cells (HUVEC). Methods: Confluent HUVEC at passage levels 3 and 4 were exposed to increasing doses of LPS (1– 1000 ng/ml) for 4 h at 37°C and prepro ET-1 mRNA accumulation and big ET-1 and ET-1 concentrations in the conditioned medium were measured. Results: Endotoxin had a dual effect on HUVEC. LPS at doses ranging between 250 and 1000 ng/ml induced progressive diminution in ET-1 concentration in the culture medium. However, lower LPS concentrations dose-dependently increased big ET-1 and ET-1 release by HUVEC without altering prepro ET-1 mRNA expression. Conclusions: These results suggest that low LPS concentrations promote ET-1 release in HUVEC by a post-transcriptional mechanism located upstream of big ET-1 in the biosynthetic pathway of ET-1. These findings could explain the existence of high circulating levels of ET-1 in cirrhosis in spite of transcriptional activation of prepro ET-1 mRNA only occurring in the liver.