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.

APPROACH AND 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: Jinlong He, Yanhong Zhou, Junjie Xing, Qilong Wang, Huaiping Zhu, Yi Zhu, Ming-Hui Zou
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 33 Issue 6 Pg. 1297-305 (Jun 2013) ISSN: 1524-4636 [Electronic] United States
• PMID: 23539217 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• Receptors, Thromboxane
• Vascular Cell Adhesion Molecule-1
• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
• Protein Serine-Threonine Kinases
• STK11 protein, human
• rho-Associated Kinases
• AMP-Activated Protein Kinase Kinases

Topics

• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid (metabolism, pharmacology)
• AMP-Activated Protein Kinase Kinases
• Animals
• Cell Adhesion (drug effects)
• Cell Movement (physiology)
• Cells, Cultured
• Endothelial Cells (drug effects, metabolism)
• Human Umbilical Vein Endothelial Cells
• Humans
• Mice
• Models, Animal
• NF-kappa B (antagonists & inhibitors, metabolism)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Receptors, Thromboxane (metabolism)
• Sensitivity and Specificity
• Vascular Cell Adhesion Molecule-1 (metabolism)
• Vasculitis (metabolism, physiopathology)
• rho-Associated Kinases (metabolism)