title: 4-Phenylbutyric acid suppresses inflammation through regulation of endoplasmic reticulum stress of endothelial cells stimulated by uremic serum.
abstract: OBJECTIVE
  Endoplasmic reticulum (ER) stress is involved in the pathogenesis of atherosclerosis (AS). Endothelial cell (EC) dysfunction and monocyte migration to the subendothelium are considered to be essential manifestations of AS. We conducted this study to determine whether ER stress was involved in uremic serum-induced EC dysfunction and whether the regulation of ER stress using a chemical chaperone 4-phenylbutyric acid (4-PBA) had a preventative effect.
  
  
  METHODS
  Human umbilical vein endothelial cells (HUVECs) were divided into 4 groups: a control serum group (C.S), a uremic serum group (U.S), a uremic serum plus 4-PBA (5mM) treatment group (4-PBA), and a uremic serum plus pyrrolidine dithiocarbamate (PDTC:50 μM) treatment group (PDTC).
  
  
  RESULTS
  Lower concentrations of uremic serum (<10%) facilitated the proliferation of HUVECs. In contrast, the proliferative capability of HUVECs was gradually decreased when we continuously increased the concentration of uremic serum. Compared with C.S, HUVEC incubation with uremic serum had high expression levels of GRP78, p-PERK, NF-κB, MCP-1, and VEGF. THP-1 migration was markedly higher than C.S over the indicated time. These alterations were inhibited by the administration of 4-PBA.
  
  
  CONCLUSIONS
  These findings suggest that regulation of ER stress coupled with inflammatory activation by 4-PBA would be a promising therapy to reverse the process and development of uremic serum-induced EC dysfunction.
authors.affiliation: Institute of Nephrology of Chongqing and Department of Nephrology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zeng
authors.affiliation: Institute of Nephrology of Chongqing and Department of Nephrology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, PR China.
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Guo
authors.affiliation: Institute of Nephrology of Chongqing and Department of Nephrology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Qi
authors.affiliation: Institute of Nephrology of Chongqing and Department of Nephrology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, PR China.
authors.forename: Ji-Gang
authors.initials: JG
authors.lastname: Chen
authors.affiliation: Institute of Nephrology of Chongqing and Department of Nephrology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, PR China.
authors.forename: Li-Ling
authors.initials: LL
authors.lastname: Yang
authors.affiliation: Institute of Nephrology of Chongqing and Department of Nephrology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, PR China.
authors.forename: Zhi-Feng
authors.initials: ZF
authors.lastname: Luo
authors.affiliation: Institute of Nephrology of Chongqing and Department of Nephrology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, PR China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Mu
authors.affiliation: Institute of Nephrology of Chongqing and Department of Nephrology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, PR China. Electronic address: fxb12@aliyun.com.
authors.forename: Bing
authors.initials: B
authors.lastname: Feng
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000032:analysis; D003470:Culture Media; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000517:prevention & control*; D016328:NF-kappa B / Q000187:drug effects; D010654:Phenylbutyrates / Q000494:pharmacology*; D014511:Uremia / Q000097:blood*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D003470:Culture Media; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D016328:NF-kappa B; D010654:Phenylbutyrates; D042461:Vascular Endothelial Growth Factor A; C075773:4-phenylbutyric acid
keywords: 4-Phenylbutyric acid; Atherosclerosis; Chronic renal failure; Endoplasmic reticulum stress; Inflammatory activation