The dysregulated proliferation, migration, apoptosis and angiogenesis of endothelial cells are involved in diabetic endothelial dysfunction. The circulating salusin-beta levels were increased in diabetic patients, and salusin-beta contributes to diabetic cardiomyopathy in rats. However, the roles of salusin-beta in diabetes mellitus-induced endothelial dysfunction are not fully understood. Herein, we demonstrated the increased expressions of salusin-beta in human umbilical vein endothelial cells (HUVECs) cultured in HG medium. Exposure of HUVECs to HG inhibited the proliferation, migration, and angiogenesis, retarded cell cycle progression of endothelial cells, which were rescued by knockdown of salusin-beta. We also established that silencing of salusin-beta with adenoviruse-mediated shRNA reduced high glucose-induced apoptosis by up-regulating Bcl-2 expression and down-regulating Bax and caspase-3 expressions. Blockade of salusin-beta ameliorated HG-induced suppression of adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Of note, pretreatment with AMPK inhibitor Compound C abolished salusin-beta silencing-mediated endothelial protective effects. In summary, our results highlighted the involvement of salusin-beta in HG-related endothelial dysfunction, and salusin-beta contributed high glucose-induced endothelial injury via inactivation of AMPK signaling pathway. (C) 2017 Elsevier Inc. All rights reserved.