title: Valsartan independent of AT₁ receptor inhibits tissue factor, TLR-2 and -4 expression by regulation of Egr-1 through activation of AMPK in diabetic conditions.
abstract: Patients suffering from diabetes mellitus (DM) are at a severe risk of atherothrombosis. Early growth response (Egr)-1 is well characterized as a central mediator in vascular pathophysiology. We tested whether valsartan independent of Ang II type 1 receptor (AT1R) can reduce tissue factor (TF) and toll-like receptor (TLR)-2 and -4 by regulating Egr-1 in THP-1 cells and aorta in streptozotocin-induced diabetic mice. High glucose (HG, 15 mM) increased expressions of Egr-1, TF, TLR-2 and -4 which were significantly reduced by valsartan. HG increased Egr-1 expression by activation of PKC and ERK1/2 in THP-1 cells. Valsartan increased AMPK phosphorylation in a concentration and time-dependent manner via activation of LKB1. Valsartan inhibited Egr-1 without activation of PKC or ERK1/2. The reduced expression of Egr-1 by valsartan was reversed by either silencing Egr-1, or compound C, or DN-AMPK-transfected cells. Valsartan inhibited binding of NF-κB and Egr-1 to TF promoter in HG condition. Furthermore, valsartan reduced inflammatory cytokine (TNF-α, IL-6 and IL-1β) production and NF-κB activity in HG-activated THP-1 cells. Interestingly, these effects of valsartan were not affected by either silencing AT1R in THP-1 cells or CHO cells, which were devoid of AT1R. Importantly, administration of valsartan (20 mg/kg, i.p) for 8 weeks significantly reduced plasma TF activity, expression of Egr-1, TLR-2, -4 and TF in thoracic aorta and improved glucose tolerance of streptozotocin-induced diabetic mice. Taken together, we concluded that valsartan may reduce atherothrombosis in diabetic conditions through AMPK/Egr-1 regulation.
authors.affiliation: Department of Pharmacology, College of Medicine, Yeungnam University, Daegu, Korea.
authors.forename: Yu Mi
authors.initials: YM
authors.lastname: Ha
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Park
authors.forename: Young Jin
authors.initials: YJ
authors.lastname: Kang
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Park
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Ki Churl
authors.initials: KC
authors.lastname: Chang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051766:Early Growth Response Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D005951:Glucose Tolerance Test; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology*; D013925:Thromboplastin / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D034741:RNA, Small Interfering; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D000068756:Valsartan; D013925:Thromboplastin; D055372:AMP-Activated Protein Kinases; D014633:Valine
keywords: AMPK; Egr-1; atherothrombosis; diabetes; valsartan
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