(Circulation. 1997;96:2262-2271.)
© 1997 American Heart Association, Inc.
Articles |
Advanced Glycation End Product (AGE)–Mediated Induction of Tissue Factor in Cultured Endothelial Cells Is Dependent on RAGE
From the Department of Internal Medicine I, University of Heidelberg (A.B., P.W., R.Z., P.P.N.), Germany; the Institute of Pathology (T.I., T.L., M.M.) and the Institute of Anatomy, Technical University Dresden (M.K.), Germany; the Allgemeines Krankenhaus Wien (P.Q.), Vienna, Austria; and Asta Medica (H.T.), Frankfurt, Germany.
Correspondence to P.P. Nawroth, MD, Medizinische Klinik I, Bergheimer Str 58, 69115 Heidelberg, Germany.
Background Binding of advanced glycation end
products (AGEs) to the cellular surface receptor (RAGE) induces
translocation of the transcription factor NF-
B into the nucleus and
NF-B–mediated gene expression. This study examines the role of RAGE
in the AGE albumin–mediated induction of
endothelial tissue factor, known to be partly
controlled by NF-B.
Methods and Results Endothelial cells (ECs)
were incubated in the presence of an 18-mer phosphorothioate
oligodeoxynucleotide antisense to the 5'-coding sequence of
the RAGE gene (antisense RAGE; 0.1 µmol/L). Sense
oligonucleotides (sense RAGE, 0.1 µmol/L) of the
same region served as control. The cellular uptake of
oligonucleotides was controlled by
immunofluorescence microscopy. RAGE transcription
was suppressed by antisense RAGE, as demonstrated by RT-PCR reactions.
AGE albumin–mediated activation of cultured ECs was studied
after 48 hours of preincubation of ECs with antisense or sense RAGE.
Electrophoretic mobility shift assays and Western blot analysis
demonstrated that the AGE albumin–induced translocation of
NF-B from the cytoplasm into the nucleus was suppressed in the
presence of antisense RAGE but not by sense RAGE. In parallel, AGE
albumin–mediated tissue factor transcription, activity, and
antigen were significantly reduced in ECs exposed to antisense RAGE,
whereas sense RAGE (and nonspecific oligonucleotides)
did not influence tissue factor expression.
Conclusions Activation of ECs and induction of tissue factor by AGE albumin in ECs is dependent on RAGE.
Key Words: arteriosclerosis • atherosclerosis • coagulation • diabetes mellitus • endothelium
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