Zinc supplementation protects against diabetic endothelial dysfunction via GTP cyclohydrolase 1 restoration.

ABSTRACT

This study explored whether zinc supplementation alleviates diabetic endothelial dysfunction and the possible mechanisms underlying. We found that high glucose exposure significantly increased reactive oxygen species (ROS) and decreased guanosine 5'-triphosphate cyclohydrolase 1 (GTPCH1) and tetrahydrobiopterin (BH4) levels in bovine aortic endothelial cells (BAECs) in a time-dependent manner. High glucose increased zinc release from GTPCH1 in a similar trend. Zinc supplementation restored GTPCH1 and BH4 levels and blocked ROS accumulation in both BACEs and wild type GTPCH1 transfected HEK293 cells, but not in the zinc-free C141R mutant of GTPCH1 transfected ones. In vivo experiments showed that exogenous supplementation of zinc to streptozotocin (STZ)-induced diabetic mice partially improved the impaired maximal endothelium-dependent vasorelaxation, reversed the aberrant reduction of GTPCH1 and BH4, and suppressed the elevation of ROS in the aortas. In conclusion, our study demonstrated a novel mechanism that via GTPCH1 restoration zinc supplementation exerts a protective benefit on diabetic endothelial dysfunction.