title: Oxidized high-density lipoprotein impairs endothelial progenitor cells' function by activation of CD36-MAPK-TSP-1 pathways.
abstract: OBJECTIVE
  High-density lipoprotein (HDL) levels inversely correlate with cardiovascular events due to the protective effects on vascular wall and stem cells, which are susceptible to oxidative modifications and then lead to potential pro-atherosclerotic effects. We proposed that oxidized HDL (ox-HDL) might lead to endothelial progenitor cells (EPCs) dysfunction and investigated underlying mechanisms.
  
  
  RESULTS
  ox-HDL was shown to increase apoptosis and intracellular reactive oxygen species levels, but to reduce migration, angiogenesis, and cholesterol efflux of EPCs in a dose-dependent manner. p38 mitogen-activated protein kinase (MAPK) and NF-κB were activated after ox-HDL stimulation, which also upregulated thrombospondin-1 (TSP-1) expression without affecting vascular endothelial growth factor. Effects caused by ox-HDL could be significantly attenuated by pretreatment with short hairpin RNA-mediated CD36 knockdown or probucol. Data of in vivo experiments and the inverse correlation of ox-HDL and circulating EPC numbers among patients with coronary artery diseases (CAD) or CAD and type 2 diabetes also supported it. Meanwhile, HDL separated from such patients could significantly increase cultured EPC's caspase 3 activity, further supporting our proposal.
  
  
  METHODS
  This is the most complete study to date of how ox-HDL would impair EPCs function, which was involved with activation of CD36-p38 MAPK-TSP-1 pathways and proved by not only the inverse relationship between ox-HDL and circulating EPCs in clinic but also pro-apoptotic effects of HDL separated from patients' serum.
  
  
  CONCLUSIONS
  Activation of CD36-p38 MAPK-TSP-1 pathways contributes to the pathological effects of ox-HDL on EPCs' dysfunction, which might be one of the potential etiological factors responsible for the disturbed neovascularization in chronic ischemic disease.
authors.affiliation: 1 Department of Cardiology, Shanghai Changzheng Hospital, Second Military Medical University , Shanghai, People's Republic of China .
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Wu
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: He
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Feng
authors.initials: F
authors.lastname: Wu
authors.forename: Ru
authors.initials: R
authors.lastname: Ding
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Ren
authors.forename: Qijun
authors.initials: Q
authors.lastname: Jiang
authors.forename: Min
authors.initials: M
authors.lastname: Fan
authors.forename: Chun
authors.initials: C
authors.lastname: Liang
authors.forename: Zonggui
authors.initials: Z
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D002465:Cell Movement; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D003324:Coronary Artery Disease / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood; D066026:Endothelial Progenitor Cells / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D008075:Lipoproteins, HDL / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D018919:Neovascularization, Physiologic; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D018955:CD36 Antigens; D008075:Lipoproteins, HDL; D016328:NF-kappa B; D017382:Reactive Oxygen Species; C481348:SPZ1 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D002784:Cholesterol