Homocysteine, a risk factor for premature vascular disease and thrombosis, induces tissue factor activity in endothelial cells.
Elevated blood levels of homocysteine represent an independent risk factor for premature arterial vascular disease and thrombosis. We investigated whether homocysteine could induce tissue factor (TF) procoagulant activity in cultured human endothelial cells. Homocysteine increased cellular TF activity in a time- and concentration-dependent manner. Low concentrations of homocysteine (0.1 to 0.6 mmol/L), similar to those found in the blood of patients with homocystinuria, enhanced TF activity by 25% to 100%. Other sulfur-containing amino acids (cystine, homocystine, cysteine, and methionine) induced less TF activity than did homocysteine; however, beta-mercaptoethanol and dithiothreitol were more effective than homocysteine in increasing TF activity. Preincubation of homocysteine with a sulfhydryl inhibitor such as N-ethylmaleimide prevented homocysteine induction of TF activity. A quantitative polymerase chain reaction method indicated that homocysteine increased TF mRNA in endothelial cells. These results indicate that an atherogenic amino acid, homocysteine, can initiate coagulation by the TF pathway through a mechanism involving the free thiol group of the amino acid and by TF gene transcription. These data support the hypothesis that perturbation of vascular coagulant mechanisms may contribute to the thrombotic tendency seen in patients with homocystinuria.
Fryer
R H
RH
Department of Medicine, University of Utah Medical Center, Salt Lake City 84132.
Wilson
B D
BD
Gubler
D B
DB
Fitzgerald
L A
LA
Rodgers
G M
GM
D001483:Base Sequence; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006710:Homocysteine / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis; D012307:Risk Factors; D013925:Thromboplastin / Q000096:biosynthesis* / Q000235:genetics; D013927:Thrombosis / Q000209:etiology*; D014652:Vascular Diseases / Q000209:etiology*
D012333:RNA, Messenger; D006710:Homocysteine; D013925:Thromboplastin