Metformin inhibits intracranial aneurysm formation and progression by regulating vascular smooth muscle cell phenotype switching via the AMPK/ACC pathway
Metformin inhibits intracranial aneurysm formation and progression by regulating vascular smooth muscle cell phenotype switching via the AMPK/ACC pathway
复制标题
二甲双胍通过 AMPK/ACC 通路调节血管平滑肌细胞表型转换来抑制颅内动脉瘤的形成和进展
DOI：
10.1186/s12974-020-01868-4
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发表时间：
2020-06-16
影响因子：
9.3
通讯作者：
Zhu, Wei
中科院分区：
文献类型：
--
作者：
Li, Sichen;Shi, Yuan;Zhu, Wei
背景血管平滑肌细胞（VSMC）表型的调节在颅内动脉瘤（IA）的形成和进展中起着重要作用。然而，其潜在机制仍不清楚。甲氨蝶呤是一种5 'AMP活化蛋白激酶（AMPK）激动剂，对血管系统具有保护作用。本研究探讨二甲双胍是否通过AMPK/乙酰辅酶A羧化酶（ACC）途径调节IA发病过程中VSMC表型转换。方法采用弹性蛋白酶诱导的IA大鼠模型，建立IA大鼠模型。研究了二甲双胍对AMPK活化和VSMC表型调节的影响。我们还建立了血小板源性生长因子（PDGF）-BB诱导的VSMC模型，并分析了不同剂量的二甲双胍、AMPK拮抗剂、ACC拮抗剂及其组合下的表型变化，包括增殖、迁移和凋亡以及AMPK/ACC轴激活。结果二甲双胍可降低IA的发生率和破裂率，并通过激活AMPK/ACC通路诱导VSMC表型由收缩型向合成型转变，表现为VSMC特异性基因表达上调和促炎细胞因子水平降低。AMPK/ACC轴激活抑制VSMCs的增殖、迁移和凋亡，其中PDGF-BB诱导VSMCs表型转换。结论二甲双胍通过抑制VSMC的表型转换、增殖、迁移和凋亡，保护血管内皮细胞免受IA的形成和破裂。因此，二甲双胍具有预防IA的治疗潜力。
Background The regulation of vascular smooth muscle cell (VSMC) phenotype plays an important role in intracranial aneurysm (IA) formation and progression. However, the underlying mechanism remains unclear. Metformin is a 5 ' AMP-activated protein kinase (AMPK) agonist that has a protective effect on vasculature. The present study investigated whether metformin modulates VSMC phenotype switching via the AMPK/acetyl-CoA carboxylase (ACC) pathway during IA pathogenesis. Methods Adult male Sprague-Dawley rats (n= 80) were used to establish an elastase-induced IA model. The effects of metformin on AMPK activation and VSMC phenotype modulation were examined. We also established a platelet-derived growth factor (PDGF)-BB-induced VSMC model and analyzed changes in phenotype including proliferation, migration, and apoptosis as well as AMPK/ACC axis activation under different doses of metformin, AMPK antagonist, ACC antagonist, and their combinations. Results Metformin decreased the incidence and rupture rate of IA in the rat model and induced a switch in VSMC phenotype from contractile to synthetic through activation of the AMPK/ACC pathway, as evidenced by upregulation of VSMC-specific genes and decreased levels of pro-inflammatory cytokines. AMPK/ACC axis activation inhibited the proliferation, migration, and apoptosis of VSMCs, in which phenotypic switching was induced by PDGF-BB. Conclusions Metformin protects against IA formation and rupture by inhibiting VSMC phenotype switching and proliferation, migration, and apoptosis. Thus, metformin has therapeutic potential for the prevention of IA.