Transforming growth factor-beta(1) modulates oxidatively modified LDL-induced expression of adhesion molecules: role of LOX-1.
Oxidatively modified LDL (ox-LDL) activates a lectin-like receptor, LOX-1, which results in the expression of adhesion molecules on endothelial surface. We investigated the regulation of the expression of transforming growth factor-beta(1) (TGF-beta(1)) and its receptors by ox-LDL and the functional significance of this interaction with regard to adhesion molecule expression in human coronary artery endothelial cells (HCAECs). Ox-LDL, in a time- and concentration-dependent manner, upregulated the expression of all 3 subtypes (1, 2, and 3 [including endoglin]) of TGF-beta(1) receptors and decreased active TGF-beta(1) synthesis (all P<0.05 versus control and native-LDL-treated cells). Treatment of HCAECs with a monoclonal antibody to LOX-1 attenuated ox-LDL-mediated upregulation of TGF-beta(1) receptors and decrease in TGF-beta(1) synthesis (P<0.05 versus ox-LDL alone). Ox-LDL also enhanced the expression of P-selectin and ICAM-1 as well as monocyte adhesion to HCAECs (P<0.05 versus control untreated cells). Pretreatment with recombinant TGF-beta(1) attenuated the enhanced expression of adhesion molecules and monocyte adhesion to HCAECs (P<0.05 versus ox-LDL alone). Effects of recombinant TGF-beta(1) were blocked by antibody to TGF-beta(1) receptor type 2, but not by antibody to endoglin. Thus ox-LDL, via activation of LOX-1, increases the expression of TGF-beta(1) receptors and decreases TGF-beta(1) synthesis in HCAECs. Recombinant TGF-beta(1), by binding to TGF-beta(1) type 2 receptors, modulates ox-LDL-mediated expression of adhesion molecules and monocyte adhesion to HCAECs.
Chen
H
H
Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA.
Li
D
D
Saldeen
T
T
Mehta
J L
JL
D000906:Antibodies / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D002460:Cell Line; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000096:biosynthesis / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051131:Receptors, Oxidized LDL; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis; D051127:Scavenger Receptors, Class E; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
D000906:Antibodies; D015815:Cell Adhesion Molecules; D003432:Cross-Linking Reagents; D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; D019007:P-Selectin; D012333:RNA, Messenger; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; D018125:Receptors, Transforming Growth Factor beta; D051127:Scavenger Receptors, Class E; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C099252:oxidized low density lipoprotein; D018799:Intercellular Adhesion Molecule-1