Yamagishi Sho-ichi, Matsui Takanori, Nakamura Kazuo, Inoue Hiroyoshi, Takeuchi Masayoshi, Ueda Seiji, Fukami Kei, Okuda Seiya, Imaizumi Tsutomu
Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan.
Microvasc Res. 2008 Jan;75(1):130-4. doi: 10.1016/j.mvr.2007.05.001. Epub 2007 May 18.
We have previously shown that advanced glycation end products (AGEs)-their receptor (RAGE) interaction elicits angiogenesis through autocrine production of vascular endothelial growth factor (VEGF), thus suggesting the active involvement of the AGEs-RAGE system in proliferative diabetic retinopathy (PDR). Since the crosstalk between the AGEs-RAGE and the renin-angiotensin system has also been proposed in the pathogenesis of PDR, we investigated here whether olmesartan, an angiotensin II type 1 receptor blocker, inhibited the AGEs-elicited angiogenesis in vitro by suppressing the NF-kappaB-mediated RAGE expression. Olmesartan significantly inhibited the AGEs-induced NF-kappaB promoter activity and RAGE gene expression in cultured microvascular endothelial cells (ECs). Further, olmesartan was found to block the AGEs-induced up-regulation of VEGF mRNA levels and consequent increase in DNA synthesis in ECs. These results demonstrated for the first time that olmesartan inhibited the AGEs signaling to angiogenesis by suppressing RAGE expression in ECs. Our present study suggests that blockade of the renin-angiotensin system by olmesartan may play a protective role against PDR by attenuating the deleterious effects of AGEs via down-regulation of RAGE.
我们之前已经表明，晚期糖基化终末产物（AGEs）与其受体（RAGE）的相互作用通过血管内皮生长因子（VEGF）的自分泌产生引发血管生成，从而提示AGEs-RAGE系统积极参与增殖性糖尿病视网膜病变（PDR）。由于在PDR的发病机制中也有人提出AGEs-RAGE与肾素-血管紧张素系统之间存在相互作用，我们在此研究了奥美沙坦（一种血管紧张素II 1型受体阻滞剂）是否通过抑制NF-κB介导的RAGE表达来抑制体外AGEs引发的血管生成。奥美沙坦显著抑制培养的微血管内皮细胞（ECs）中AGEs诱导的NF-κB启动子活性和RAGE基因表达。此外，发现奥美沙坦可阻断AGEs诱导的ECs中VEGF mRNA水平上调以及随后的DNA合成增加。这些结果首次证明，奥美沙坦通过抑制ECs中的RAGE表达来抑制AGEs对血管生成的信号传导。我们目前的研究表明，奥美沙坦对肾素-血管紧张素系统的阻断可能通过下调RAGE减轻AGEs的有害作用，从而对PDR起到保护作用。
