title: C-reactive protein attenuates endothelial progenitor cell survival, differentiation, and function: further evidence of a mechanistic link between C-reactive protein and cardiovascular disease.
abstract: BACKGROUND
  Myocardial ischemia provides a potent stimulus to angiogenesis, and the mobilization and differentiation of endothelial progenitor cells (EPCs) has been shown to be important in this process. An elevated level of C-reactive protein (CRP) has emerged as one of the most powerful predictors of cardiovascular disease. However, the impact of CRP on EPC biology is unknown.
  
  
  RESULTS
  EPCs were isolated from the peripheral venous blood of healthy male volunteers. Cells were cultured in endothelial cell basal medium-2 in the absence and presence of CRP (5 to 20 microg/mL), rosiglitazone (1 micromol/L), and/or vascular endothelial growth factor. EPC differentiation, survival, and function were assayed. CRP at concentrations > or =15 microg/mL significantly reduced EPC cell number, inhibited the expression of the endothelial cell-specific markers Tie-2, EC-lectin, and VE-cadherin, significantly increased EPC apoptosis, and impaired EPC-induced angiogenesis. EPC-induced angiogenesis was dependent on the presence of nitric oxide, and CRP treatment caused a decrease in endothelial nitric oxide synthase mRNA expression by EPCs. However, all of these detrimental CRP-mediated effects on EPCs were attenuated by pretreatment with rosiglitazone, a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist.
  
  
  CONCLUSIONS
  Human recombinant CRP, at concentrations known to predict adverse vascular outcomes, directly inhibits EPC differentiation, survival, and function, key components of angiogenesis and the response to chronic ischemia. This occurs in part via an effect of CRP to reduce EPC eNOS expression. The PPARgamma agonist rosiglitazone inhibits the negative effects of CRP on EPC biology. The ability of CRP to inhibit EPC differentiation and survival may represent an important mechanism that further links inflammation to cardiovascular disease.
authors.affiliation: Division of Cardiac Surgery, Toronto General Hospital, 14EN-215, 200 Elizabeth St, Toronto, Ontario, Canada M5G 2C4. subodh.verma@sympatico.ca
authors.forename: Subodh
authors.initials: S
authors.lastname: Verma
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kuliszewski
authors.forename: Shu-Hong
authors.initials: SH
authors.lastname: Li
authors.forename: Paul E
authors.initials: PE
authors.lastname: Szmitko
authors.forename: Liana
authors.initials: L
authors.lastname: Zucco
authors.forename: Chao-Hung
authors.initials: CH
authors.lastname: Wang
authors.forename: Mitesh V
authors.initials: MV
authors.lastname: Badiwala
authors.forename: Donald A G
authors.initials: DA
authors.lastname: Mickle
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.forename: Paul W M
authors.initials: PW
authors.lastname: Fedak
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Stewart
authors.forename: Michael J B
authors.initials: MJ
authors.lastname: Kutryk
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002097:C-Reactive Protein / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002318:Cardiovascular Diseases / Q000209:etiology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004790:Enzyme Induction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists / Q000096:biosynthesis / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D045162:Thiazolidinediones; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D000077154:Rosiglitazone; D009569:Nitric Oxide; D002097:C-Reactive Protein; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III