Stereospecific and redox-sensitive increase in monocyte adhesion to endothelial cells by homocysteine.
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.


RESULTS
L-Hcy, but not D-Hcy, increases the production of reactive oxygen species inside EC, enhances nuclear factor(NF)-kappaB 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-kappaB activation abolished Hcy-induced monocyte adhesion, ICAM-1 expression, and nuclear translocation of NF-kappaB.


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.
Postea
Otilia
O
Medical Policlinic, Ludwig-Maximilians University Munich, Germany.
Krotz
Florian
F
Henger
Anna
A
Keller
Christiane
C
Weiss
Norbert
N
D050197:Atherosclerosis / Q000276:immunology* / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D006710:Homocysteine / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007536:Isomerism; D007948:Leukemia, Monocytic, Acute; D008968:Molecular Conformation; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013450:Sulfones / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D014657:Vasculitis / Q000276:immunology / Q000378:metabolism
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D016328:NF-kappa B; D009570:Nitriles; D017382:Reactive Oxygen Species; D013450:Sulfones; D006710:Homocysteine; D013481:Superoxides; D018799:Intercellular Adhesion Molecule-1