Verma Subodh, Kuliszewski Michael A, Li Shu-Hong, Szmitko Paul E, Zucco Liana, Wang Chao-Hung, Badiwala Mitesh V, Mickle Donald A G, Weisel Richard D, Fedak Paul W M, Stewart Duncan J, Kutryk Michael J B
Division of Cardiac Surgery, Toronto General Hospital, 14EN-215, 200 Elizabeth St, Toronto, Ontario, Canada M5G 2C4.
Circulation. 2004 May 4;109(17):2058-67. doi: 10.1161/01.CIR.0000127577.63323.24. Epub 2004 Apr 12.
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.
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.
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.
心肌缺血对血管生成具有强大的刺激作用，内皮祖细胞（EPCs）的动员和分化在此过程中起着重要作用。C反应蛋白（CRP）水平升高已成为心血管疾病最有力的预测指标之一。然而，CRP对EPC生物学特性的影响尚不清楚。
从健康男性志愿者的外周静脉血中分离出EPCs。将细胞在无CRP（5至20微克/毫升）、罗格列酮（1微摩尔/升）和/或血管内皮生长因子存在的情况下，在内皮细胞基础培养基-2中培养。检测EPC的分化、存活和功能。浓度≥15微克/毫升的CRP显著减少EPC细胞数量，抑制内皮细胞特异性标志物Tie-2、EC-凝集素和VE-钙黏蛋白的表达，显著增加EPC凋亡，并损害EPC诱导的血管生成。EPC诱导的血管生成依赖于一氧化氮的存在，CRP处理导致EPC内皮型一氧化氮合酶mRNA表达降低。然而，罗格列酮（一种过氧化物酶体增殖物激活受体-γ（PPARγ）激动剂）预处理可减弱CRP对EPC的所有这些有害作用。
已知可预测不良血管结局的浓度的人重组CRP直接抑制EPC的分化、存活和功能，这些是血管生成和对慢性缺血反应的关键组成部分。这部分是通过CRP降低EPC eNOS表达的作用实现的。PPARγ激动剂罗格列酮可抑制CRP对EPC生物学特性的负面影响。CRP抑制EPC分化和存活的能力可能代表了一种将炎症与心血管疾病进一步联系起来的重要机制。
