Pathobiological role of advanced glycation endproducts via mitogen-activated protein kinase dependent pathway in the diabetic vasculopathy
Pathobiological role of advanced glycation endproducts via mitogen-activated protein kinase dependent pathway in the diabetic vasculopathy
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DOI：
10.3858/emm.2008.40.4.398
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发表时间：
2008-08-31
影响因子：
12.8
通讯作者：
Kwon, Hyuck Moon
中科院分区：
文献类型：
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作者：
Yoon, Young Won;Kang, Tae Soo;Kwon, Hyuck Moon
晚期糖基化终产物（AGEs）参与了糖尿病冠状动脉支架术后的新生内膜形成和支架内再狭窄（ISR）的发生，但AGEs在血管平滑肌细胞增殖中的作用机制尚不清楚。我们试图确定AGEs相关的糖尿病血管病变的病理生物学机制。用不同浓度的AGEs培养大鼠主动脉平滑肌细胞（RAoSMC），观察其增殖情况。用免疫组化法检测人颈动脉粥样硬化组织中AGEs受体的表达。Western blotting检测MAP激酶系统在培养的RAoSMC中的激活情况。AGEs可促进RAoSMC增殖，并与ERK和p38激酶磷酸化水平增加呈时间和剂量依赖性。RNA干扰可降低MAP激酶活性。AGEs刺激增加了培养的RAoSMC中活性氧（ROS）的产生。从这项研究中得出结论，AGEs通过MAP激酶依赖的途径在RAoSMC增殖中发挥关键作用。MAP激酶系统激活血管平滑肌细胞（VSMC）增殖，增加ROS生成可能是AGEs诱导糖尿病血管病变的机制。
Advanced glycation endproducts (AGEs) have been reported to play a role in neointimal formation and increase the rate of in-stent restenosis (ISR) in the diabetic coronary artery disease patients treated with stents, but the potential pathogenic mechanisms of AGEs in vascular smooth muscle cell proliferation remain unclear. We sought to determine the AGEs related pathobiological mechanism of diabetic vasculopathy. Rat aortic smooth muscle cell (RAoSMC) culture was done with different concentrations of AGEs and proliferation was assessed. Immunohistochemistry for receptor of AGEs (RAGE) was performed with human carotid atheroma. Western blotting was performed to assess the activation of MAP kinase system in the cultured RAoSMC. AGEs increased RAoSMC proliferation and were associated with increased phosphorylation of ERK and p38 kinase by time and dose dependent manner. The MAP kinase activity was decreased by RNA interference for RAGE. AGEs stimulation increased reactive oxygen species (ROS) generation in cultured RAoSMC. From this study it is concluded that AGEs played a key role in RAoSMC proliferation via MAP kinase dependent pathways. Activation of vascular smooth muscle cell (VSMC) proliferation by MAP kinase system and increased formation of ROS may be the possible mechanisms of AGEs induced diabetic vasculopathy.