Effect of advanced glycation end-products on gene expression and synthesis of TNF-alpha and endothelial nitric oxide synthase by endothelial cells.
BACKGROUND
Advanced glycation end-products (AGEs), which are formed in aging, diabetes mellitus, and kidney failure are implicated in the occurrence of vascular complications. We, thus, evaluated in cultured endothelial cells, the AGEs' effect on gene expression and synthesis of tumor necrosis factor-alpha (TNF-alpha) and endothelial nitric oxide synthase (eNOS) mRNA and protein expression, which may be involved in vascular remodeling.


METHODS
Human umbilical vein cords endothelial cells (HUVEC) were stimulated with AGE-specific compounds [AGE-human serum albumin (AGE-HSA), N(epsilon)-carboxymethylysine (CML), AGE-beta2 microglobulin (AGE-beta2m)], and thereafter, incubated with interleukin1-alpha, lipopolysaccharide, and interferon-gamma.


RESULTS
mRNA expression and secretion of TNF-alpha were significantly enhanced after incubation with AGE-HSA, CML, and AGE-beta2m compared to that found in HUVEC incubated with HSA or beta2m. AGE-HSA, CML, and AGE-beta2m induced a significant decrease in eNOS protein and mRNA expression.


CONCLUSIONS
AGEs promote mRNA expression and secretion of TNF-alpha and reduce eNOS mRNA and protein expression in HUVEC. Such changes may play a role in the vascular dysfunction and the development of vasculopathy seen in diabetes, uremia, and old age.
Department of Nephrology and Hypertension, Sapir Medical Center, Meir General Hospital, Kfar-Saba and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Gloriar@clalit.org.il
Gloria
G
Rashid
Sydney
S
Benchetrit
Dina
D
Fishman
Jacques
J
Bernheim
D000906:Antibodies / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D012333:RNA, Messenger / Q000032:analysis; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000276:immunology; D012709:Serum Albumin / Q000494:pharmacology*; D000075462:Serum Albumin, Human; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D014471:Umbilical Veins / Q000166:cytology
D000906:Antibodies; D000970:Antineoplastic Agents; D017127:Glycation End Products, Advanced; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D012709:Serum Albumin; D014409:Tumor Necrosis Factor-alpha; C109748:advanced glycation end products-human serum albumin; C048496:N(6)-carboxymethyllysine; D007371:Interferon-gamma; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D008239:Lysine; D000075462:Serum Albumin, Human