Studies on the mechanism of sodium butyrate-stimulated t-PA expression in cultured human endothelial cells. Effects of trichostain A and 2-deoxy-D-glucose

Abstract

Summary We have found that the induction of tissue-type plasminogen activator (t-PA) by sodium butyrate in human umbilical vein endothelial cells (HUVEC) can be mimicked with a structurally unrelated, specific histone deacetylase-inhibitor, (R)-trichostatin A (TSA). Simultaneous addition of butyrate and TSA at concentrations approaching maximal induction by the compounds alone showed no additive effect on t-PA stimulation, indicating a common regulatory mechanism, i.e. histone acetylation. A decrease in butyrate-stimulated t-PA production with the glucose analogue, 2-deoxy-D-glucose, was part of a general decrease in protein secretion, possibly as a result of an impaired glycosylation. The altered glycosylation pattern of t-PA could be visualized by fibrin-underlay autography. The effects of 2-deoxy-D-glucose could be overcome by the simultaneous addition of mannose to the medium. Our results suggest an important role of histone acetylation in the butyrate-induced stimulation of t-PA expression in HUVEC.