Inflammatory cytokines and fatty acids regulate endothelial cell heparanase expression.
Heparan sulfates, the carbohydrate chains of heparan sulfate proteoglycans, play an important role in basement membrane organization and endothelial barrier function. We explored whether endothelial cells secrete a heparan sulfate degrading heparanase under inflammatory conditions and what pathways were responsible for heparanase expression. Heparanase mRNA and protein by Western blot were induced when cultured endothelial cells were treated with cytokines, oxidized low-density lipoprotein (LDL) or fatty acids. Heparanase protein in the cell media was induced 2-10-fold when cells were treated with tumor necrosis factor alpha (TNFalpha) or interleukin 1beta (IL-1beta). Vascular endothelial growth factor (VEGF), in contrast, decreased heparanase secretion. Inhibitors to nuclear factor-kappaB (NFkappaB), PI3-kinase, MAP kinase, or c-jun kinase (JNK) did not affect TNFalpha-induced heparanase secretion. Interestingly, inhibition of caspase-8 completely abolished heparanase secretion induced by TNFalpha. Fatty acids also induced heparanase, and this required an Sp1 site in the heparanase promoter. Immunohistochemical analyses of cross sections of aorta showed intense staining for heparanase in the endothelium of apoE-null mice but not wild-type mice. Thus, heparanase is an inducible inflammatory gene product that may play an important role in vascular biology.
Chen
Guangping
G
Department of Medicine, Columbia University, New York, New York 10032, USA.
Wang
Dongyan
D
Vikramadithyan
Reeba
R
Yagyu
Hiroaki
H
Saxena
Uday
U
Pillarisetti
Sivaram
S
Goldberg
Ira J
IJ
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D015153:Blotting, Western; D002417:Cattle; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology*; D005227:Fatty Acids / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005966:Glucuronidase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000494:pharmacology; D007668:Kidney / Q000166:cytology*; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D013997:Time Factors; D000099175:Heparanase
D016207:Cytokines; D005227:Fatty Acids; D005966:Glucuronidase; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; D008156:Luciferases; D012333:RNA, Messenger; D000099175:Heparanase