Cardiology Division, National Health Insurance Corporation, Ilsan Hospital, Goyang 410-719, Korea.
Exp Mol Med. 2009 Nov 30;41(11):802-11. doi: 10.3858/emm.2009.41.11.086.
Advanced glycation endproducts (AGEs)-induced vascular smooth muscle cell (VSMCs) proliferation and formation of reactive oxygen species (ROS) are emerging as one of the important mechanisms of diabetic vasculopathy but little is known about the antioxidative action of HMG CoA reductase inhibitor (statin) on AGEs. We hypothesized that statin might reduce AGEs-induced intracellular ROS of VSMCs and analyzed the possible mechanism of action of statin in AGEs-induced cellular signaling. Aortic smooth muscle cell of Sprague-Dawley rat (RASMC) culture was done using the different levels of AGEs stimulation in the presence or absence of statin. The proliferation of RASMC, ROS formation and cellular signaling was evaluated and neointimal formation after balloon injury in diabetic rats was analyzed. Increasing concentration of AGEs stimulation was associated with increased RASMC proliferation and increased ROS formation and they were decreased with statin in a dose-dependent manner. Increased NF-kappaB p65, phosphorylated ERK, phosphorylated p38 MAPK, cyclooxygenase-2, and c-jun by AGEs stimulation were noted and their expression was inhibited by statin. Neointimal formation after balloon injury was much thicker in diabetic rats than the sham-treated group but less neointimal growth was observed in those treated with statin after balloon injury. Increased ROS formation, subsequent activation of MAPK system and increased VSMC proliferation may be possible mechanisms of diabetic vasculopathy induced by AGEs and statin may play a key role in the treatment of AGEs-induced diabetic atherosclerosis.
晚期糖基化终产物（AGEs）诱导的血管平滑肌细胞（VSMCs）增殖和活性氧（ROS）的形成，正成为糖尿病血管病变的重要机制之一，但对于羟甲基戊二酰辅酶 A 还原酶抑制剂（他汀类药物）对 AGEs 的抗氧化作用知之甚少。我们假设他汀类药物可能会减少 AGEs 诱导的 VSMCs 内 ROS，并分析了他汀类药物在 AGEs 诱导的细胞信号转导中的可能作用机制。采用不同浓度的 AGEs 刺激，在存在或不存在他汀类药物的情况下，对 Sprague-Dawley 大鼠（RASMC）的主动脉平滑肌细胞进行培养。评估了 RASMC 的增殖、ROS 的形成和细胞信号转导，并分析了糖尿病大鼠球囊损伤后的内膜新生情况。随着 AGEs 刺激浓度的增加，RASMC 的增殖和 ROS 的形成增加，而随着他汀类药物剂量的增加，它们呈剂量依赖性减少。AGEs 刺激导致 NF-kappaB p65、磷酸化 ERK、磷酸化 p38 MAPK、环氧化酶-2 和 c-jun 的表达增加，而这些表达可被他汀类药物抑制。与假手术组相比，糖尿病大鼠球囊损伤后的内膜新生更厚，但在球囊损伤后用他汀类药物治疗的大鼠中，内膜新生较少。ROS 形成增加、随后的 MAPK 系统激活和 VSMC 增殖增加，可能是 AGEs 诱导的糖尿病血管病变的机制，而他汀类药物可能在治疗 AGEs 诱导的糖尿病动脉粥样硬化中发挥关键作用。
