Modification of tissue-factor mRNA and protein response to thrombin and interleukin 1 by high glucose in cultured human endothelial cells.
Because diabetic vascular disease is accompanied by a state of hypercoagulability, manifested by increased thrombin activity and foci of intravascular coagulation, we investigated whether a specific procoagulant property of the endothelium--production and surface expression of tissue factor--is modified by elevated glucose concentrations. In unperturbed human vascular endothelial cells, tissue factor mRNA and expression of the functional protein were undetectable and were not induced by 10-12 days of exposure to 30 mM glucose. In thrombin-stimulated cultures, tissue-factor expression was related inversely to cellular density, with confluent cultures producing (per 10(5) cells) half the amount of tissue factor measured in sparse cultures. Cells exposed to high glucose and studied when cell number and thymidine incorporation were identical to control cells manifested increased tissue-factor mRNA level and functional protein production in response to thrombin (P = .002). This effect was not attributable to hypertonicity and was not observed after short exposure to high glucose. In contrast, the tissue-factor response to interleukin 1, a modulator of endothelial function in the context of host defense, was decreased in cells cultured in high glucose (P = .04). These findings indicate that exposure to high glucose can alter tissue-factor gene expression in perturbed vascular endothelium. The reciprocal effects of high glucose on the tissue-factor response to thrombin and interleukin 1 points to different pathways of tissue-factor stimulation by the two agents and suggests functional consequences pertinent to the increased thrombin activity and compromised host-defense mechanisms observed in diabetes.
Department of Medicine, University of California, San Diego.
D
D
Boeri
F E
FE
Almus
M
M
Maiello
E
E
Cagliero
L V
LV
Rao
M
M
Lorenzi
D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D005796:Genes / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D006982:Hypertonic Solutions; D007375:Interleukin-1 / Q000502:physiology*; D007700:Kinetics; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics*; D011994:Recombinant Proteins / Q000494:pharmacology*; D013917:Thrombin / Q000502:physiology*; D013925:Thromboplastin / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D014471:Umbilical Veins
D006982:Hypertonic Solutions; D007375:Interleukin-1; D012333:RNA, Messenger; D011994:Recombinant Proteins; D013925:Thromboplastin; D013917:Thrombin; D005947:Glucose