High glucose-induced apoptosis in human vascular endothelial cells is mediated through NF-κB and c-Jun NH2-terminal kinase pathway and prevented by PI3K/Akt/eNOS pathway

Published on Mar 1, 2006in Cellular Signalling3.388
· DOI :10.1016/j.cellsig.2005.05.009
Feng Ming Ho10
Estimated H-index: 10
Wan-Wan Lin45
Estimated H-index: 45
(NTU: National Taiwan University)
+ 6 AuthorsChiau S. Liau1
Estimated H-index: 1
(NTU: National Taiwan University)
Abstract Our 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.
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