title: Liver kinase B1 is required for thromboxane receptor-dependent nuclear factor-κB activation and inflammatory responses.
abstract: OBJECTIVE
  Thromboxane A2 receptor (TPr) has been reported to trigger vascular inflammation. Nuclear factor κ B (NF-κB) is a known transcription factor. The aims of the present study were to determine the contributions of NF-κB activation to TPr-triggered vascular inflammation and elucidate the mechanism(s) underlying TPr activation of NF-κB.
  
  
  RESULTS
  The effects of TPr activators, [1S-[1 alpha,2 alpha(Z),3beta(1E,3S*), 4 alpha]]-7-[3-[3-hydroxy-4-(4-iodophenoxy)-1-butenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (I-BOP) and U46619, on NF-κB activation, phosphorylation of rhoA/rho-associated kinases and liver kinase B1, cell adhesion and migration, proliferation, and endothelium-dependent vasorelaxation were assayed in cultured human umbilical vein endothelial cells, human monocytes, or isolated mouse aortas. Exposure of human umbilical vein endothelial cells to TPr agonists I-BOP and U46619 induced dose-dependent and time-dependent phosphorylation of inhibitor of κB α in parallel with aberrant expression of inflammatory markers cyclooxygenase-2, inducible nitric oxide synthase, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1. Inhibition of NF-κB by pharmacological or genetic means abolished TPr-triggered expression of inflammatory markers. Consistently, exposure of human umbilical vein endothelial cells to either I-BOP or U46619 significantly increased phosphorylation of inhibitor of κB α, I kappaB kinase, rhoA, rho-associated kinases, and liver kinase B1. Pretreatment of human umbilical vein endothelial cells with the TPr antagonist SQ29548 or rho-associated kinases inhibitor Y27632 or silencing of the LKB1 blocked TPr-enhanced phosphorylation of inhibitor of κB α and its upstream kinase, I kappaB kinase. Finally, exposure of isolated mouse aortas to either U46619 or I-BOP enhanced NF-κB activation and vascular inflammation in parallel with reduced endothelium-dependent relaxation in intact vessels.
  
  
  CONCLUSIONS
  TPr stimulation instigates aberrant inflammation and endothelial dysfunction via rho-associated kinases/liver kinase B1/I kappaB kinase-dependent NF-κB activation in vascular endothelial cells.
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China.
authors.forename: Jinlong
authors.initials: J
authors.lastname: He
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Zhou
authors.forename: Junjie
authors.initials: J
authors.lastname: Xing
authors.forename: Qilong
authors.initials: Q
authors.lastname: Wang
authors.forename: Huaiping
authors.initials: H
authors.lastname: Zhu
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zou
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000378:metabolism / Q000494:pharmacology; D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D023421:Models, Animal; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017482:Receptors, Thromboxane / Q000378:metabolism*; D012680:Sensitivity and Specificity; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014657:Vasculitis / Q000378:metabolism / Q000503:physiopathology; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D017482:Receptors, Thromboxane; D019010:Vascular Cell Adhesion Molecule-1; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D054460:rho-Associated Kinases; D000091162:AMP-Activated Protein Kinase Kinases
keywords: COX-2; LKB1; NF-κB; endothelial cell; inflammation
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