Telmisartan inhibits AGE-induced C-reactive protein production through downregulation of the receptor for AGE via peroxisome proliferator-activated receptor-gamma activation
Telmisartan inhibits AGE-induced C-reactive protein production through downregulation of the receptor for AGE via peroxisome proliferator-activated receptor-gamma activation
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DOI：
10.1007/s00125-006-0437-7
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发表时间：
2006-12-01
期刊：
影响因子：
8.2
通讯作者：
Sata, M.
中科院分区：
文献类型：
--
作者：
Yoshida, T.;Yamagishi, S.;Sata, M.
目的/假设C-反应蛋白（CRP），一种主要由肝脏产生的急性期反应物，在糖尿病中升高，从而促进动脉粥样硬化的发展和进展。然而，糖尿病中CRP升高的分子机制尚未完全了解。由于AGE和血管紧张素II（Ang II）之间的相互作用已被提出在糖尿病加速动脉粥样硬化的发病机制中，我们在这里研究了替米沙坦，一种独特的Ang II 1型受体阻滞剂（ARB），（PPAR-gamma）调节活性，可以抑制人肝癌细胞系中AGE诱导的CRP表达，方法用蛋白质印迹法分析AGE受体（AGE）的蛋白质水平。通过定量实时RT-PCR分析基因表达。用ELISA测定释放到培养基中的CRP。结果替米沙坦可剂量依赖性地下调ARB细胞内活性氧（ROS）的表达，坎地沙坦则无此作用。在Hep 3B细胞中，替米沙坦降低基础以及AGE诱导的Bcl-2蛋白表达。此外，在Hep 3B细胞中，替米沙坦剂量依赖性地抑制AGE诱导的ROS生成以及随后的CRP基因和蛋白诱导。GW 9662，一种抑制剂的PPAR-gamma，阻断了替米沙坦的抑制作用，在Hep 3B cells.Conclusions/interpretation中的Tissue表达及其下游信号转导我们目前的研究表明一个独特的有益方面的替米沙坦：它可以作为一种抗炎剂对AGE抑制Tissue表达通过PPAR-gamma激活在肝脏中，并可能发挥保护作用，在糖尿病血管损伤。
Aims/hypothesis C-reactive protein (CRP), an acute-phase reactant produced mainly by the liver, is elevated in diabetes, thus contributing to the development and progression of atherosclerosis. However, the molecular mechanism underlying the elevation of CRP in diabetes is not fully understood. Since a crosstalk between AGE and angiotensin II (Ang II) has been proposed in the pathogenesis of accelerated atherosclerosis in diabetes, we examined here whether and how telmisartan, a unique Ang II type 1 receptor blocker (ARB) with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-modulating activity, could inhibit AGE-induced CRP expression in a human hepatoma cell line, Hep3B cells.Methods Protein levels of the receptor for AGE (RAGE) were analysed by western blots. Gene expression was analysed by quantitative real-time RT-PCR. CRP released into the medium was measured with ELISA. Intracellular formation of reactive oxygen species (ROS) was measured using the fluorescent probe CM-H(2)DCFDA.Results Telmisartan, but not candesartan, another ARB, downregulated RAGE mRNA levels in a dose-dependent manner. Telmisartan decreased basal as well as AGE-induced RAGE protein expression in Hep3B cells. Furthermore, telmisartan dose-dependently inhibited AGE-induced ROS generation and subsequent CRP gene and protein induction in Hep3B cells. GW9662, an inhibitor of PPAR-gamma, blocked the inhibitory effects of telmisartan on RAGE expression and its downstream signalling in Hep3B cells.Conclusions/interpretation Our present study indicates a unique beneficial aspect of telmisartan: it may work as an anti-inflammatory agent against AGE by suppressing RAGE expression via PPAR-gamma activation in the liver and may play a protective role in vascular injury in diabetes.