(Hypertension. 2001;38:48.)
© 2001 American Heart Association, Inc.
Scientific Contribution |
Endothelial Apoptosis Induced by Oxidative Stress Through Activation of NF-
B
Antiapoptotic Effect of Antioxidant Agents on Endothelial Cells
From the Department of Geriatric Medicine (M.A., H.M., H.N., K. Yamamoto, K. Yamazaki, T.O.) and the Division of Gene Therapy (T.N., R.M., M.N., Y.K.), Osaka University Medical School, Osaka, Japan.
Correspondence to Ryuichi Morishita MD, PhD, Associate Professor, Division of Gene Therapy Science, Osaka University Medical School, 2 to 2 Yamada-oka, Suita, Osaka 565 to 0871, Japan. E-mail morishit{at}geriat.med.osaka-u.ac.jp
Abstract—— Injury of endothelial cells has been assumed to be an initial trigger of the development of atherosclerosis. In this study, we investigated the molecular mechanisms of endothelial cell death induced by hypoxia, which leads to oxidative stress. To study the relation between hypoxia-induced cell death and activation of nuclear factor-
B (NF-B) in a hypoxic state, we evaluated the effect of 2 antioxidant drugs, probucol and pyrrolidine dithiocarbamate (PDTC), on human endothelial apoptosis. Although hypoxic treatment of human aortic endothelial cells resulted in a significant decrease in cell number and a significant increase in apoptotic cells compared with that of cells under normoxia (P<0.01), treatment with probucol (50 µmol/L) or PDTC (100 µmol/L) significantly attenuated the decrease in cell number (P<0.01) and was accompanied by inhibition of NF-B activation. Furthermore, downregulation of bcl-2 caused by hypoxia was inhibited by these drugs. We further investigated the translocation of bax protein from the cytoplasm to the mitochondrial heavy fraction membrane, as translocation of bax protein is considered to be a determinant of apoptosis. Interestingly, we found that antioxidant treatment inhibited the translocation of bax protein caused by hypoxia. Moreover, upregulation of p53, a proapoptotic molecule, was observed in hypoxia, whereas treatment with probucol attenuated the expression of p53 accompanied by suppression of NF-B activation. These data suggest functional links between p53 and endothelial apoptosis through the activation of NF-B. Overall, the current study demonstrated that oxidative stress induced apoptosis in human aortic endothelial cells through the downregulation of bcl-2, translocation of bax, and upregulation of p53, probably through NF-B activation. Oxidative stress may play an important role in endothelial apoptosis mediated by hypoxia, through the activation of NF-B.
Key Words: hypoxia • apoptosis • endothelium-derived factors • bax
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