Prostaglandin E1 Inhibited Diabetes-Induced Phenotypic Switching of Vascular Smooth Muscle Cells Through Activating Autophagy
Prostaglandin E1 Inhibited Diabetes-Induced Phenotypic Switching of Vascular Smooth Muscle Cells Through Activating Autophagy
复制标题
前列腺素 E1 通过激活自噬抑制糖尿病诱导的血管平滑肌细胞表型转换。
DOI：
10.1159/000494240
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Xu, Ming
中科院分区：
文献类型：
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作者：
An, Xing-Rong;Li, Xin;Xu, Ming
背景/目的：血管平滑肌细胞(VSMCs)的表型转换与2型糖尿病(T2 DM)动脉粥样硬化形成过程的发生或发展有关。前列地尔(PGE1)作为一种生物活性药物，对血管功能具有保护作用。然而，目前尚不清楚PGE1是否通过自噬抑制VSMCs的表型转换，从而在糖尿病血管并发症中起到保护作用。方法：用高糖(HG，25 mM)诱导VSMC表型转换，免疫印迹分析和免疫荧光染色检测VSMC的蛋白表达。在体实验中，高脂饲料(HFD)联合小剂量链脲佐菌素(STZ)喂养的大鼠出现血管损伤和功能障碍。结果：HG处理的VSMCs-SMA减少，Vimentin、I型胶原和增殖细胞核抗原(PCNA)表达增加。随着p62丰度的增加，暴露于汞的VSMC自噬标志物LC3B和Beclin-1显著降低。这种异常变化被PGE1显著逆转，PGE1模仿自噬激活剂雷帕霉素的作用，并被自噬抑制剂3-甲基腺嘌呤戏剧性地抵消。此外，PGE1抑制AKT和mTOR的磷酸化，从而负性调节VSMC的自噬水平。体内实验表明，前列腺素E_1能显著改善T2 DM大鼠非内皮依赖性胸主动脉收缩，并能恢复T2 DM大鼠动脉中膜中-SMA、骨桥蛋白、LC3B、磷酸化mTOR的表达。结论：PGE1通过AKT/mTOR依赖的自噬机制维持VSMCs的表型，从而预防糖尿病血管并发症。(C)2018年作者(S)由S.Karger AG，巴塞尔出版
Background/Aims: The phenotype switching of vascular smooth muscle cells (VSMCs) was associated with the onset or progression of the atherogenic process in type 2 diabetes mellitus (T2DM). Alprostadil (Prostaglandin E1, PGE1) as a bioactive drug had a protective effect on vascular function. However, it is unknown whether PGE1 inhibited the phenotype switching in VSMCs via autophagy, which played a protective role in the vascular complications of diabetes. Methods: The phenotype switching was induced by high glucose (HG, 25mM) in VSMCs, the protein expression was measured by western blot analysis and immunofluorescent staining. In vivo study, vascular lesion and dysfunction were produced in the rats fed with high fat diet (HFD) combined with low dose streptozotocin (STZ) administration. Results: The decrease of -SMA and the increase of vimentin, collagen I and proliferating cell nuclear antigen (PCNA) were found in HG-treated VSMCs. Along with more abundance of p62, autophagy markers LC3B and Beclin-1 significantly decreased in VSMCs exposed to HG. Such abnormal changes were significantly reversed by PGE1, which mimicked the role of autophagy activator rapamycin and was dramatically counteracted by 3-methyladenine, an autophagy inhibitor. Furthermore, PGE1 suppressed the phosphorylation of AKT and mTOR, which negatively regulated autophagy level in VSMCs. In vivo study, PGE1 remarkably improved the endothelium-independent contraction of thoracic aorta and restored the expression of -SMA, osteopontin, LC3B, phosphorylated mTOR in the artery media of T2DM rats. Conclusion: These results demonstrated that PGE1 maintained the phenotype of VSMCs via the AKT/mTOR-dependent autophagy, which prevented diabetes-induced vascular complications. (c) 2018 The Author(s) Published by S. Karger AG, Basel