title: Uric acid promotes chemokine and adhesion molecule production in vascular endothelium via nuclear factor-kappa B signaling.
abstract: OBJECTIVE
  Hyperuricemia is an important risk factor for atherosclerosis, yet the potential mechanisms are not well understood. Migration and adhesion of leukocytes to endothelial cells play key roles in initiation and development of atherosclerosis. We investigated monocyte-endothelial cell interactions and potential signaling pathways under uric acid (UA)-stimulated conditions.
  
  
  RESULTS
  Primary human umbilical vein endothelial cells (HUVECs) were cultured and exposed to different concentrations of UA for various periods. Experimental hyperuricemia rat models were established. Expression of chemoattractant protein-1 (MCP-1), interleukin 8 (IL-8), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were evaluated. Monocyte-endothelial cell interactions were elucidated by chemotaxis and adhesion assays, and nuclear factor-kappa B (NF-κB) pathway was studied using fluorescent microscopy and electrophoretic mobility shift assay. Results showed that high concentration of UA stimulated generation of chemokines and adhesion molecules in ex vivo and in vivo experiments. Migration and adhesion of human monocytic leukemia cell line THP-1 cells to HUVECs were promoted and activated NF-κB was significantly increased. UA-induced responses were ameliorated by organic anion transporter inhibitor probenecid and NF-κB inhibitor BAY11-7082. It was also observed that human endothelial cells expressed urate transporter-1, which was not regulated by UA.
  
  
  CONCLUSIONS
  High concentration of UA exerts unfavorable effects directly on vascular endothelium via the NF-κB signaling pathway, the process of which requires intracellular uptake of UA.
authors.affiliation: Department of Geriatrics, Peking University First Hospital, Beijing, China.
authors.forename: W Y
authors.initials: WY
authors.lastname: Liang
authors.affiliation: Department of Cardiology, Peking University Shougang Hospital, Beijing, China.
authors.forename: X Y
authors.initials: XY
authors.lastname: Zhu
authors.affiliation: Department of Geriatrics, Peking University First Hospital, Beijing, China.
authors.forename: J W
authors.initials: JW
authors.lastname: Zhang
authors.affiliation: Department of Geriatrics, Peking University First Hospital, Beijing, China.
authors.forename: X R
authors.initials: XR
authors.lastname: Feng
authors.affiliation: Department of Geriatrics, Peking University First Hospital, Beijing, China.
authors.forename: Y C
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Department of Geriatrics, Peking University First Hospital, Beijing, China. Electronic address: meilinliu@yahoo.com.
authors.forename: M L
authors.initials: ML
authors.lastname: Liu
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D033461:Hyperuricemia / Q000097:blood / Q000150:complications; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000187:drug effects; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology; D014527:Uric Acid / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; C491766:Ccl2 protein, rat; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D018925:Chemokines; D016209:Interleukin-8; D016328:NF-kappa B; D009570:Nitriles; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; D013450:Sulfones; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D014527:Uric Acid
keywords: Adhesion molecules; Atherosclerosis; Chemokines; Hyperuricemia; NF-κB; Uric acid