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1653309 
Journal Article 
C-reactive protein attenuates endothelial progenitor cell survival, differentiation, and function: further evidence of a mechanistic link between C-reactive protein and cardiovascular disease 
Verma, S; Kuliszewski, MA; Li, SH; Szmitko, PE; Zucco, L; Wang, CH; Badiwala, MV; Mickle, DA; Weisel, RD; Fedak, PW; Stewart, DJ; Kutryk, MJ 
2004 
Yes 
Circulation
ISSN: 0009-7322
EISSN: 1524-4539 
109 
17 
2058-2067 
English 
15078802 
WOS:000221173900005 
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.

METHODS AND 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. 
C-reactive protein; cells; apoptosis; nitric oxide synthase