Department of Medicine, University of Hong Kong, Hong Kong.
Atherosclerosis. 2010 Mar;209(1):173-7. doi: 10.1016/j.atherosclerosis.2009.08.031. Epub 2009 Aug 21.
The receptor for advanced glycation end-products (RAGE) plays an important role in the pathogenesis of diabetic complications and atherosclerosis. Interfering with the activation of RAGE by using a soluble form of the receptor (sRAGE) ameliorates the vascular complications of diabetes in animal models. We have investigated whether statin can influence the expression of sRAGE and esRAGE (a splice variant of sRAGE) in vitro and in vivo.
THP-1 cells were incubated with atorvastatin in vitro and sRAGE and esRAGE in the medium was measured by Western immunoblot. Serum levels of sRAGE and esRAGE were measured by ELISA in archived serum samples from a previous randomized double-blind placebo-controlled clinical trial that explored the cardiovascular effects of atorvastatin in hypercholesterolemic Chinese type 2 diabetic patients.
sRAGE and esRAGE were induced by atorvastatin in a time- and dose-dependent manner in THP-1 cells. In the diabetic patients, there was a significant increase in serum sRAGE (p<0.05) and esRAGE (p<0.01) in the atorvastatin group at 6-month, but no change in placebo group. Serum esRAGE was higher in atorvastatin group than placebo group [median 240.5pg/ml (interquartile range 186.5-377.3) vs 194.8pg/ml (124.1-347.9) respectively, p<0.01] at 6-month, whereas the differences in sRAGE did not reach statistical significance (p=0.051). There was a correlation between the increase of serum esRAGE and reduction of serum LDL (r=-0.36, p=0.001).
Statins are known to have pleiotropic effects and we have shown that atorvastatin can increase circulating esRAGE levels in type 2 diabetic patients.
晚期糖基化终产物受体（RAGE）在糖尿病并发症和动脉粥样硬化的发病机制中发挥重要作用。通过使用受体的可溶性形式（sRAGE）干扰 RAGE 的激活，可以改善动物模型中糖尿病的血管并发症。我们研究了他汀类药物是否可以影响体外和体内 sRAGE 和 esRAGE（sRAGE 的剪接变体）的表达。
将 THP-1 细胞与阿托伐他汀在体外孵育，并通过 Western 免疫印迹法测量培养基中的 sRAGE 和 esRAGE。通过 ELISA 测量来自先前的随机、双盲、安慰剂对照临床试验的存档血清样本中的血清 sRAGE 和 esRAGE 水平，该试验探索了阿托伐他汀在患有高胆固醇血症的中国 2 型糖尿病患者中的心血管作用。
阿托伐他汀以时间和剂量依赖的方式诱导 THP-1 细胞中 sRAGE 和 esRAGE 的产生。在糖尿病患者中，阿托伐他汀组在 6 个月时血清 sRAGE（p<0.05）和 esRAGE（p<0.01）显著增加，但安慰剂组没有变化。阿托伐他汀组血清 esRAGE 高于安慰剂组[中位数 240.5pg/ml（四分位距 186.5-377.3）比 194.8pg/ml（124.1-347.9），p<0.01]，而 sRAGE 的差异没有达到统计学意义（p=0.051）。血清 esRAGE 的增加与血清 LDL 的降低呈相关（r=-0.36，p=0.001）。
他汀类药物具有多种作用，我们已经表明阿托伐他汀可以增加 2 型糖尿病患者循环中的 esRAGE 水平。
