title: Interaction between the polyol pathway and non-enzymatic glycation on aortic smooth muscle cell migration and monocyte adhesion.
abstract: We investigated for the interaction between the polyol pathway and enhanced non-enzymatic glycation, both implicated in the pathogenesis of diabetic atherosclerosis, in the activation of aortic smooth muscle cell (SMC) function. Mouse aortas and primary cultures of SMCs from wildtype (WT) mice and transgenic (TG) mice expressing human aldose reductase (AR) were studied regarding changes in AR activity, and SMC gene activation, migration and monocyte adhesion, in response to advanced glycation end-product modified BSA (AGE-BSA). Results showed that AGE-BSA increased AR activity in both WT and TG aortas, with greater increments (p < 0.05) in TG aortas which, basally, had elevated AR activity (2.8 fold of WT). These increments were attenuated by zopolrestat, an AR inhibitor. Similar AGE-induced increments in AR activity were observed in primary cultures of aortic SMCs from WT and TG mice (60% and 100%, respectively, P < 0.01). Such increments were accompanied by increases in intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) mRNA levels (both P < 0.05), activation of membrane-associated PKC-beta1 (P < 0.05) as well as increased SMC migration and Tamm-Horsfall protein (THP)-1 monocyte adhesion to SMCs (both p < 0.01), with all changes being significantly greater in TG SMCs (P < 0.05) and suppressible by either zopolrestat or transfection with an AR antisense oligonucleotide. Our findings suggest that the effects of AGEs on SMC activation, migration and monocyte adhesion are mediated partly through the polyol pathway and, possibly, PKC activation. The greater AGE-induced changes in the TG SMCs have provided further support for the dependency of such changes on polyol pathway hyperactivity.
authors.affiliation: Department of Medicine, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong SAR, China.
authors.forename: Qinghong
authors.initials: Q
authors.lastname: Dan
authors.forename: Rachel
authors.initials: R
authors.lastname: Wong
authors.forename: Sookja K
authors.initials: SK
authors.lastname: Chung
authors.forename: Stephen S M
authors.initials: SS
authors.lastname: Chung
authors.forename: Karen S L
authors.initials: KS
authors.lastname: Lam
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism; D052160:Benzothiazoles; D015152:Blotting, Northern; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000166:cytology / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology; D010793:Phthalazines / Q000494:pharmacology; D011108:Polymers / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012710:Serum Albumin, Bovine / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D052160:Benzothiazoles; C491768:Ccl2 protein, mouse; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; C489275:Hint1 protein, mouse; C480027:ICAM-2 protein, mouse; D009419:Nerve Tissue Proteins; D020320:Oligoribonucleotides, Antisense; D010793:Phthalazines; D011108:Polymers; D012333:RNA, Messenger; D013844:Thiazoles; C081628:advanced glycation end products-bovine serum albumin; C024617:polyol; C067172:zopolrestat; D012710:Serum Albumin, Bovine; D000449:Aldehyde Reductase