title: A potent soluble epoxide hydrolase inhibitor, t-AUCB, acts through PPARγ to modulate the function of endothelial progenitor cells from patients with acute myocardial infarction.
abstract: BACKGROUND
  Epoxyeicosatrienoic acids (EETs) are natural angiogenic mediators regulated by soluble epoxide hydrolase (sEH). Inhibitors of sEH can stabilize EETs levels and were reported to reduce atherosclerosis and inhibit myocardial infarction in animal models. In this work, we investigated whether increasing EETs with the sEH inhibitor t-AUCB would increase angiogenesis related function in endothelial progenitor cells (EPCs) from patients with acute myocardial infarction (AMI).
  
  
  RESULTS
  EPCs were isolated from 50 AMI patients and 50 healthy subjects (control). EPCs were treated with different concentrations of t-AUCB for 24h with or without peroxisome proliferator activated receptor γ (PPARγ) inhibitor GW9662. Migration of EPCs was assayed in trans-well chambers. Angiogenesis assays were performed using a Matrigel-Matrix in vitro model. The expression of vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF-1α) mRNA and protein in EPCs was measured by real-time PCR or Western blot, respectively. Also, the concentration of EETs in the culture supernatant was detected by ELISA. The activity of EPCs in the AMI patient group was reduced compared to healthy controls. Whereas increasing EET levels with t-AUCB promoted a dose dependent angiogenesis and migration in EPCs from AMI patients. Additionally, the t-AUCB dose dependently increased the expression of the angiogenic factors VEGF and HIF-α. Lastly, we provide evidence that these effects were PPARγ dependent.
  
  
  CONCLUSIONS
  The results demonstrate that the sEH inhibitor positively modulated the functions of EPCs in patients with AMI through the EETs-PPARγ pathway. The present study suggests the potential utility of sEHi in the therapy of ischemic heart disease.
authors.affiliation: Department of Cardiology, Second Xiangya Hospital, Central South University, Changsha 410011, PR China. xudanyan02@sina.com
authors.forename: Dan-yan
authors.initials: DY
authors.lastname: Xu
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Davis
authors.forename: Zhen-he
authors.initials: ZH
authors.lastname: Wang
authors.forename: Shui-ping
authors.initials: SP
authors.lastname: Zhao
authors.forename: Binaya
authors.initials: B
authors.lastname: Wasti
authors.forename: Zhe-liang
authors.initials: ZL
authors.lastname: Liu
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.forename: Nipavan
authors.initials: N
authors.lastname: Chiamvimonvat
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
mesh_terms: D000368:Aged; D000813:Anilides / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000201:enzymology*; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000502:physiology*; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C457499:2-chloro-5-nitrobenzanilide; C524106:4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid; D000813:Anilides; D001565:Benzoates; D004791:Enzyme Inhibitors; D047495:PPAR gamma; D014508:Urea; D004851:Epoxide Hydrolases