Priming effect of homocysteine on inducible vascular cell adhesion molecule-1 expression in endothelial cells.
Hyperhomocysteinemia is an independent risk factor for the development of atherosclerosis, as well as for arterial and venous thrombosis. However, the mechanisms through which elevated circulating levels of homocysteine cause vascular injury and promote thrombosis remain unclear. Here, we tested the hypothesis that homocysteine (Hcy) sensitizes endothelial cells to the effect of inflammatory mediators. Human umbilical vein endothelial cells (HUVEC) were incubated with Hcy 1.0 mM for varying time points, and then treated in the absence or presence of 1.5 U/ml thrombin or 10 mg/ml lipopolysaccharide (LPS). Hcy alone had no effect on the expression of vascular cell adhesion molecule (VCAM)-1. However, Hcy enhanced thrombin- and LPS-mediated induction of VCAM-1 mRNA and protein levels. Consistent with these results, pretreatment of HUVEC with Hcy resulted in a two-fold increase in LSP-mediated induction of leukocyte adhesion. The latter effect was significantly inhibited by anti-VCAM-1 antibodies. Together, these findings suggest that Hcy sensitizes HUVEC to the effect of inflammatory mediators thrombin and LPS, at least in part through VCAM-1 expression and function.
Séguin
Chantal
C
Division of Molecular and Vascular Medicine and the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. chantal.seguin@muhc.mcgill.ca
Abid
Md Ruhul
MR
Spokes
Katherine C
KC
Schoots
Ivo G
IG
Brkovic
Alexandre
A
Sirois
Martin G
MG
Aird
William C
WC
D050197:Atherosclerosis / Q000209:etiology; D002460:Cell Line; D004730:Endothelium, Vascular / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006710:Homocysteine / Q000502:physiology*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D012307:Risk Factors; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000209:etiology; D014471:Umbilical Veins / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*
D008070:Lipopolysaccharides; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; D006710:Homocysteine; D013917:Thrombin