Inhibition of neointima hyperplasia by the combined therapy of linagliptin and metformin via AMPK/Nox4 signaling in diabetic rats
Inhibition of neointima hyperplasia by the combined therapy of linagliptin and metformin via AMPK/Nox4 signaling in diabetic rats
复制标题
利格列汀和二甲双胍联合治疗通过 AMPK/Nox4 信号抑制糖尿病大鼠的新内膜增生
DOI：
10.1016/j.freeradbiomed.2019.07.030
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发表时间：
2019
影响因子：
7.4
通讯作者：
Ming Xu
中科院分区：
文献类型：
--
作者：
Wen-Xu Zhang;Guang-Jie Tai;Xiao-Xue Li;Ming Xu
背景新生内膜增生是动脉粥样硬化和再狭窄的病理基础，而动脉粥样硬化和再狭窄与糖尿病（DM）密切相关。利格列汀和二甲双胍是否能预防糖尿病引起的血管新生内膜增生仍存在争议。鉴于利格列汀和二甲双胍在临床实践中的联合治疗，我们调查了联合治疗是否抑制颈动脉新生内膜增生在糖尿病rates.Methods和resultsNeointima在颈动脉中的球囊损伤诱导大鼠喂养高脂饮食（HFD）结合低剂量链脲佐菌素（STZ）管理。体外培养的血管平滑肌细胞（VSMCs）与高糖（HG，30 mM）共同孵育，观察高糖对VSMCs增殖、迁移、凋亡及胶原沉积的影响。我们发现，利格列汀和二甲双胍联合治疗（而非单药治疗）显著抑制了糖尿病大鼠球囊损伤的贲门动脉中的新生内膜增生，并改善了内皮非依赖性收缩，这与抑制超氧化物（O2−）有关。在心脏动脉中产生。在体外实验中，HG诱导的VSMC重塑表现为PCNA、胶原1、MMP-9、Bcl-2表达显著上调，细胞迁移率显著增加，细胞凋亡率显著降低。利格列汀和二甲双胍联合使用可显著逆转此类异常变化。此外，AMP激活的蛋白激酶（AMPK）/Nox 4信号通路被发现介导了HG对VSMC的重塑反应。利格列汀和二甲双胍协同作用于高糖培养的VSMC和糖尿病大鼠贲门动脉中AMPK/Nox 4信号通路，其作用上级优于单药治疗。结论利格列汀和二甲双胍联合应用可能通过AMPK/Nox 4信号通路对VSMC重塑产生保护作用，从而改善糖尿病大鼠新生内膜增生。本研究为糖尿病相关血管狭窄的治疗提供了新的策略。
BackgroundNeointima hyperplasia is the pathological basis of atherosclerosis and restenosis which have been associated with diabetes mellitus (DM). It is controversial for linagliptin and metformin to protect against vascular neointimal hyperplasia caused by DM. Given the combined therapy of linagliptin and metformin in clinical practice, we investigated whether the combination therapy inhibited neointimal hyperplasia in the carotid artery in diabetic rats.Methods and resultsNeointima hyperplasia in the carotid artery was induced by balloon-injury in the rats fed with high fat diet (HFD) combined with low dose streptozotocin (STZ) administration. In vitro, vascular smooth muscle cells (VSMCs) were incubated with high glucose (HG, 30 mM) and the proliferation, migration, apoptosis and collagen deposition were analyzed in VSMCs. We found that the combined therapy, not the monotherapy of linagliptin and metformin significantly inhibited the neointima hyperplasia and improved the endothelium-independent contraction in the balloon-injured cardia artery of diabetic rats, which was associated with the inhibition of superoxide (O2−.) production in the cardia artery. In vitro, HG-induced VSMC remodeling was shown as the remarkable upregulation of PCNA, collagan1, MMP-9, Bcl-2 and migration rate as well as the decreased apoptosis rate. Such abnormal changes were dramatically reversed by the combined use of linagliptin and metformin. Moreover, the AMP-activated protein kinase (AMPK)/Nox4 signal pathway was found to mediate VSMC remodeling responding to HG. Linagliptin and metformin were synergistical to target AMPK/Nox4 signal pathway in VSMCs incubated with HG and in the cardia artery of diabetic rats, which was superior to the monotherapy.ConclusionsWe demonstrated that the potential protection of the combined use of linagliptin and metformin on VSMC remodeling through AMPK/Nox4 signal pathway, resulting in the improvement of neointima hyperplasia in diabetic rats. This study provided new therapeutic strategies for vascular stenosis associated with diabetes.