Ho F.M.WAN-WAN LINChen B.C.Chao C.M.CHIA-RON YANGLIAN-YU LINLai C.C.SHING-HWA LIULiau C.S.2022-09-062022-09-0620060898-6568https://www.scopus.com/inward/record.uri?eid=2-s2.0-27844593740&doi=10.1016%2fj.cellsig.2005.05.009&partnerID=40&md5=2dec10e6a14fe311077f55863a68c29dhttps://scholars.lib.ntu.edu.tw/handle/123456789/617836Our previous studies demonstrated that high glucose-induced apoptosis in human umbilical vein endothelial cells (HUVECs) is mediated by sequential activation of c-Jun N-terminal kinase (JNK) and caspase, and prevented by exogenous nitric oxide (NO). In this study we further elucidated the roles of the transcriptional factor NF-κB, phosphatidylinositol 3′-kinase (PI3K), Akt and endothelial nitric oxide synthase (eNOS) in the apoptosis of HUVECs induced by high glucose. The results showed that high glucose-induced apoptosis was significantly enhanced by PI3K inhibitors (wortmannin and LY294002), NOS inhibitor (NG-nitro-arginine methyl ester) and eNOS antisense oligonucleotide. In contrast, apoptosis was markedly reduced by NF-κB inhibitor (pyrrolidine dithiocarbamate, PDTC), NF-κB antisense oligonucleotide, NO donor (sodium nitroprusside, SNP), and overexpression of Akt. The high glucose-induced NF-κB activation and transient Akt phosphorylation were prevented by the presence of vitamin C. Moreover, high glucose-induced increase in eNOS expression was attenuated by PI3K inhibitors and the negative mutant of PI3K. The activity of JNK induced by high glucose was suppressed by NF-κB-specific antisense oligonucleotide. Taken together our results demonstrated that high glucose-induced HUVECs apoptosis is through NF-κB-dependent JNK activation and reactive oxygen species (ROS)-dependent Akt dephosphorylation. Activation of the ROS/PI3K/Akt/eNOS signaling pathway in early phase exerts protective effects against the induction of apoptosis by high glucose. © 2005 Elsevier Inc. All rights reserved.journal article10.1016/j.cellsig.2005.05.009159704292-s2.0-27844593740