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(Hypertension. 2004;43:1208.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Homocysteine Enhances Endothelial Apoptosis via Upregulation of Fas-Mediated Pathways

Toshimitsu Suhara; Keisuke Fukuo; Osamu Yasuda; Maki Tsubakimoto; Yukihiro Takemura; Hidenobu Kawamoto; Toyohiko Yokoi; Masaki Mogi; Taeko Kaimoto; Toshio Ogihara

From the Department of Geriatric Medicine, Osaka University Medical School, Japan.

Correspondence to Dr Keisuke Fukuo, Department of Geriatric Medicine, Osaka University Medical School 2-2 Yamadaoka, Suita, Osaka, Japan. E-mail fukuo{at}mwu.mukogawa-u.ac.jp

Hyperhomocysteinemia is an independent risk factor for the development of atherosclerosis. However, the underlying mechanism of endothelial cell injury in hyperhomocysteinemia has not been elucidated. In this study, we examined the effect of homocysteine (Hcy) on Fas-mediated apoptosis in endothelial cells. Hcy-induced upregulation of Fas in endothelial cells (ECs) in a dose-dependent manner. At the same time, Hcy increased intracellular peroxide in ECs. Hcy-induced Fas expression was inhibited by the treatment with catalase. Hcy increased NF-B DNA binding activity, and adenovirus-mediated transfection of a I-B mutant (I-B mt) gene inhibited Hcy-induced Fas expression. ECs were sensitive to Fas-mediated apoptosis when exposed to Hcy. Under these condition, I-B mt protected ECs from Fas-mediated apoptosis. In addition, Hcy inhibited expression of the caspase-8 inhibitor FLICE-inhibitory protein (FLIP). Adenovirus-mediated transfection of constitutively active Akt gene abolished the Hcy-mediated downregulation of FLIP. These data suggest that upregulation of Fas expression and downregulation of FLIP is a mechanism through which Hcy induces EC apoptosis.

Key Words: endothelium • apoptosis • oxidative stress • protein kinases