High-glucose-induced metallothionein expression in endothelial cells: an endothelin-mediated mechanism

Vascular endothelial cells are constantly exposed to oxidative stress and m ust be protected by physiological responses. In diabetes mellitus, endothel ial cell permeability is impaired and may be increased by high extracellula r glucose concentrations. It has been postulated that metallothionein (MT) can protect endothelial cells from oxidative stress with its increased expr ession by cytokines, thrombin, and endothelin (ET)-1. In this study, we dem onstrate that high glucose concentration can induce MT expression in endoth elial cells through a distinct ET-dependent pathway. Exposure of human umbi lical vein endothelial cells (HUVEC) to increasing concentrations of glucos e resulted in a rapid dose-dependent increase in MT-2 and ET-1 mRNA express ion. MT expression may be further augmented with addition of ET-1. Preincub ation of the cells with the specific ETB antagonist BQ-788 blocked MT-2 mRN A expression more effectively than the ETA inhibitor TBC-11251. High glucos e also increased immunoreactive MT protein expression and induced transloca tion of MT into the perinuclear area. Perinuclear localization of MT was re lated to high-glucose-induced reorganization of F-actin filaments. These re sults demonstrate that an increase in extracellular glucose in HUVEC can le ad to a rapid dose-dependent increase in MT-2 mRNA expression and to perinu clear localization of MT protein with changes to the cytoskeleton. These ef fects are mediated via the ET receptor-dependent pathway.