Department of Experimental Medicine & Biotechnology, Postgraduate Institute of Medical Education & Research, Chandigarh 160012, India.
Int J Cardiol. 2010 Jul 23;142(3):273-8. doi: 10.1016/j.ijcard.2009.01.008. Epub 2009 Feb 6.
Receptor for advanced glycation end products (RAGE) may play an important role in inflammatory processes and endothelial activation. Extracellular newly identified RAGE binding protein (EN-RAGE), natural pro-inflammatory ligand for RAGE. The role of C-reactive protein (CRP) as a mediator in inflammation and atherosclerosis is the subject of recent investigations worldwide. In the present study, we investigated the effect of CRP on RAGE and EN-RAGE gene expression in THP-1 monocytic cell line. MAP kinases (ERK, p38 and JNK) were exploited as possible signaling pathways involved in the signal transduction by CRP. Further, atorvastatin was used as a therapeutic modality for modulation of these genes in the presence of CRP.
Time and dose-dependent experiments were carried out in the presence of CRP. Specific MAPK pathways inhibitors were used to elucidate the signaling pathways involved. Effect of atorvastatin was also determined in the presence of CRP on the expression of these genes.
Time and dose-dependent experiments revealed that, treatment of THP-1 cells with 100 microg of CRP/ml/10(6) cells for 24 h, augmented the expression of RAGE and EN-RAGE genes by 2.5-3.5 folds and 3.5-4.5 folds respectively. CRP acted via FcgammaRII and utilized ERK, p38 and JNK pathways to transduce signals. Atorvastatin in a dose of 20 muM, was able to attenuate up-regulation of CRP-induced genes (p<0.01) and effects were both dose and time-dependent.
Our data strongly suggests that blockade of RAGE-EN-RAGE by statins at an early stage may prevent inflammation in atherosclerosis and counteract the harmful effects mediated by CRP.
晚期糖基化终产物受体（RAGE）可能在炎症过程和内皮细胞激活中发挥重要作用。细胞外新发现的 RAGE 结合蛋白（EN-RAGE）是 RAGE 的天然促炎配体。C 反应蛋白（CRP）作为炎症和动脉粥样硬化的介质，是目前全球研究的热点。在本研究中，我们研究了 CRP 对 THP-1 单核细胞系中 RAGE 和 EN-RAGE 基因表达的影响。细胞外信号调节激酶（ERK、p38 和 JNK）被用作 CRP 信号转导中可能涉及的信号通路。此外，阿托伐他汀被用作在 CRP 存在的情况下调节这些基因的治疗方式。
在 CRP 存在的情况下进行时间和剂量依赖性实验。使用特定的 MAPK 通路抑制剂来阐明涉及的信号通路。还确定了在 CRP 存在的情况下阿托伐他汀对这些基因表达的影响。
时间和剂量依赖性实验表明，用 100 微克 CRP/ml/10(6)细胞处理 THP-1 细胞 24 小时，可使 RAGE 和 EN-RAGE 基因的表达分别增加 2.5-3.5 倍和 3.5-4.5 倍。CRP 通过 FcγRII 作用，并利用 ERK、p38 和 JNK 途径传递信号。阿托伐他汀在 20 微摩尔的剂量下，能够减弱 CRP 诱导基因的上调（p<0.01），并且作用具有剂量和时间依赖性。
我们的数据强烈表明，在早期阶段通过他汀类药物阻断 RAGE-EN-RAGE，可能预防动脉粥样硬化中的炎症，并抵消 CRP 介导的有害影响。
