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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:508.)
© 2006 American Heart Association, Inc.

Vascular Biology

Stereospecific and Redox-Sensitive Increase in Monocyte Adhesion to Endothelial Cells by Homocysteine

Otilia Postea; Florian Krotz; Anna Henger; Christiane Keller; Norbert Weiss

From Medical Policlinic (O.P., F.K., A.H., C.K., N.W.) and the Institute of Physiology (F.K.), Ludwig-Maximilians-University Munich, Germany. O.P is currently at the Institute of Cellular Biology and Pathology "N. Simionescu," Bucharest, Romania.

Correspondence to Norbert Weiss, Medical Policlinic-Ludwig-Maximilians University, Pettenkoferstrasse 8a, D-80336 Munich, Germany. E-mail Norbert.Weiss{at}med.uni-muenchen.de

Objective— Previous studies have shown that elevated homocysteine (Hcy) levels promote the development of atherosclerotic lesions in atherosclerosis-prone animal models. There is evidence that oxidant stress contributes to Hcy’s deleterious effects on the vasculature. The accumulation and adhesion of monocytes to the vascular endothelium is a critical event in the development of atherosclerosis. We investigated the effects of Hcy on the interaction between human endothelial cells (EC) (EC line EA.hy 926 and primary human umbilical vein EC [HUVEC]) and the monocytic cell line THP-1, and the impact of vascular oxidant stress and redox-sensitive signaling pathways on these events.

Methods and Results— L-Hcy, but not D-Hcy, increases the production of reactive oxygen species inside EC, enhances nuclear factor(NF)-B activation, and stimulates intercellular adhesion molecule-1 (ICAM-1) RNA transcription and cell surface expression. This leads to a time- and dose-dependent increase in monocyte adhesion to ECs. Pretreatment of ECs with superoxide scavengers (MnTBAP and Tiron) or with an inhibitor of NF-B activation abolished Hcy-induced monocyte adhesion, ICAM-1 expression, and nuclear translocation of NF-B.

Conclusions— These findings suggest that reactive oxygen species produced under hyperhomocysteinemic conditions may induce a proinflammatory situation in the vessel wall that initiates and promotes atherosclerotic lesion development.

Incubation of endothelial cells with l-homocystein, but not with d-homocysteine, increases reactive oxygen species accumulation, activation of NF-B, and expression of ICAM-1, resulting in a time- and dose-dependent increase in monocyte adhesion to endothelial cells. Pretreatment with superoxide scavengers or an inhibitor of NF-B activation reversed all these events.

Key Words: homocysteine • endothelial dysfunction • reactive oxygen species • ICAM-1 • NF-B

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