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Diabetes 50:1472-1481, 2001
© 2001 by the American Diabetes Association, Inc.

Phosphorylation of p38 Mitogen-Activated Protein Kinase Downstream of Bax-Caspase-3 Pathway Leads to Cell Death Induced by High D-Glucose in Human Endothelial Cells

Hironori Nakagami1, Ryuichi Morishita1,2, Kei Yamamoto1, Shin-ichi Yoshimura3, Yoshiaki Taniyama1, Motokuni Aoki1, Hiroaki Matsubara4, Shokei Kim5, Yasufumi Kaneda2, and Toshio Ogihara1

1 Geriatric Medicine and
2 Gene Therapy Science, Osaka University Medical School, Suita
3 Department of Neurosurgery, Gifu University School of Medicine, Gifu
4 Department of Second Internal Medicine, Kansai Medical College, Moriguchi
5 Department of Pharmacology, Osaka City Medical College, Osaka, Japan

Because high D-glucose significantly stimulates endothelial cell death, we examined the molecular mechanisms of high D-glucose–induced endothelial apoptosis. Treatment of human aortic endothelial cells with high D-glucose (25 mmol/l), but not mannitol and L-glucose, resulted in a significant decrease in cell number and a significant increase in apoptotic cells as compared with a physiological concentration (5 mmol/l). Interestingly, high D-glucose treatment significantly increased bax protein, accompanied by translocation of bax protein from cytosol to mitochondria-enriched heavy membrane fraction. In contrast, the expression and distribution of bcl-2 protein were not altered by high D-glucose. In addition, the activity of caspase-3 proteases was increased after exposure to high glucose, whereas caspase inhibitors prevented endothelial cell death induced by high D-glucose. On the other hand, p38 mitogen-activated protein kinase (MAPK) was markedly phosphorylated and showed sustained phosphorylation after stimulation. A specific inhibitor of p38 MAPK, SB 203580, and the overexpression of kinase-inactive p38 MAPK significantly attenuated cell death induced by high D-glucose in human aortic endothelial cells, whereas at 6 h after high D-glucose treatment, SB 203580 and overexpression of kinase-inactive p38 MAPK did not attenuate caspase-3 activation induced by high D-glucose. Importantly, caspase inhibitors significantly attenuated the sustained phosphorylation of p38 MAPK induced by high D-glucose. Thus, we finally focused the MAPK kinase (MEK) kinase 1 (MEKK1) to further examine the cross-talk between p38 MAPK and the bax-caspase proteases pathway. High D-glucose treatment induced MEKK1 cleavage, whereas caspase inhibitors significantly attenuated the cleavage. Importantly, kinase-inactive MEKK1 also blocked the phosphorylation of p38 MAPK induced by high D-glucose. Here, we demonstrated that high D-glucose induced apoptosis in human endothelial cells through activation of the bax-caspase proteases pathway and through phosphorylation of p38 MAPK mediated by MEKK1. Phosphorylation of p38 MAPK downstream of the bax-caspase pathway may play a pivotal role in endothelial apoptosis mediated by high D-glucose.


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