title: Hypercholesterolemia increases the production of leukotriene B4 in neutrophils by enhancing the nuclear localization of 5-lipoxygenase.
abstract: OBJECTIVE
  Neutrophils can synthesize leukotriene B4 (LTB4) by activating the 5-lipoxygenase (5-LO)signaling pathway. LTB4 is a pro-inflammatory mediator associated with the etiology and progression of atherosclerosis. It can increase function and number of neutrophils in an autocrine manner. Since hypercholesterolemia is associated with an increase in the number and function of neutrophils, we hypothesized that this effect could be mediated through increased production of LTB4 in neutrophils.
  
  
  RESULTS
  Hypercholesterolemia was modeled in Wistar rats by feeding them with a high cholesterol diet. The induction of hypercholesterolemia caused an increase in the plasma levels of LTB4, following lipopolysaccharide stimulation. This effect was recapitulated in vitro, both in the presence and absence of stimulation with the activator of 5-LO, A23187. Neutrophils in hypercholesterolemia rats expressed similar total levels of 5-LO as control rats, but displayed increased nuclear localization of 5-LO, as well as elevated levels of phosphorylated 5-LO and ERK1/2. In vitro, MβCD/cholesterol complexes enriched cholesterol in neutrophils, resulted in similar changes in 5-LO/LTB4. In addition, these alterations could be inhibited with the ERK inhibitor PD98059.
  
  
  CONCLUSIONS
  Hypercholesterolemia increases LTB4 production in neutrophils by increasing the nuclear localization of 5-LO, which is the result of its phosphorylation by activated ERK1/2.
authors.affiliation: Cardiology Department, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Lai
authors.forename: Hua-Di
authors.initials: HD
authors.lastname: Qin
authors.forename: Lei-Lei
authors.initials: LL
authors.lastname: Guo
authors.forename: Zi-Guo
authors.initials: ZG
authors.lastname: Luo
authors.forename: Jing
authors.initials: J
authors.lastname: Chang
authors.forename: Chun-Chang
authors.initials: CC
authors.lastname: Qin
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D006937:Hypercholesterolemia / Q000378:metabolism*; D007975:Leukotriene B4 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007975:Leukotriene B4; D000001:Calcimycin; D002784:Cholesterol; D001094:Arachidonate 5-Lipoxygenase