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Metformin inhibits intracranial aneurysm formation and progression by regulating vascular smooth muscle cell phenotype switching via the AMPK/ACC pathway.

二甲双胍通过 AMPK/ACC 通路调节血管平滑肌细胞表型转换抑制颅内动脉瘤形成和进展。

  • 影响因子:5.75
  • DOI:10.1186/s12974-020-01868-4
  • 作者列表:"Li S","Shi Y","Liu P","Song Y","Liu Y","Ying L","Quan K","Yu G","Fan Z","Zhu W
  • 发表时间:2020-06-16
Abstract

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.

摘要

背景: 血管平滑肌细胞 (VSMC) 表型的调节在颅内动脉瘤 (IA) 的形成和进展中起重要作用。然而,潜在的机制仍不清楚。二甲双胍是一种 5 'AMP 激活的蛋白激酶 (AMPK) 激动剂,对脉管系统具有保护作用。本研究探讨了在 IA 发病过程中,二甲双胍是否通过 AMPK/乙酰辅酶a 羧化酶 (ACC) 途径调节 VSMC 表型转换。 方法: 采用成年雄性 Sprague-Dawley 大鼠 (n = 80) 建立弹性蛋白酶诱导的 IA 模型。检测二甲双胍对 AMPK 活化和 VSMC 表型调节的影响。我们还建立了血小板衍生生长因子 (PDGF)-BB 诱导的 VSMC 模型,分析了表型变化包括增殖、迁移、和凋亡以及不同剂量二甲双胍、 AMPK 拮抗剂、 ACC 拮抗剂及其组合下的 AMPK/ACC 轴激活。 结果: 二甲双胍降低了大鼠模型 IA 的发生率和破裂率,并通过激活 AMPK/ACC 通路诱导 VSMC 表型从收缩到合成的转换,VSMC 特异性基因的上调和促炎细胞因子水平的降低证明了这一点。AMPK/ACC 轴激活抑制 VSMCs 的增殖、迁移和凋亡,其中表型转换是由 PDGF-BB 诱导的。 结论: 二甲双胍通过抑制 VSMC 表型转换和增殖、迁移和凋亡来保护 IA 形成和破裂。因此,二甲双胍具有预防 IA 的治疗潜力。

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METHODS:BACKGROUND:Gliomas consist of a heterogeneous group of tumors. This study aimed to report the incidences of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation, 1p19q co-deletion, isocitrate dehydrogenase (IDH) gene mutations, and inactivating mutations of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) in high-grade gliomas in an ethnically diverse population. METHODS:Records of patients who underwent surgery for high-grade gliomas from January 2013 to March 2017 at our institution were obtained. The patients' age, gender, ethnicity, Karnofsky Performance Scale (KPS) score, ability to perform activities of daily living (ADLs), tumor location and biomarkers status were recorded. Data were analyzed using chi-square and Mann-Whitney U tests, Kaplan-Meier estimates and log-rank test. RESULTS:181 patients were selected (56 with grade III gliomas, 125 with grade IV gliomas). In the grade III group, 55% had MGMT promoter methylation, 41% had 1p19q co-deletion, 35% had IDH1 mutation and none had ATRX loss. In the grade IV group, 30% had MGMT promoter methylation, 2% had 1p19q co-deletion, 15% had IDH1 mutation and 8% had ATRX loss. After adjusting for effects of age, surgery and pre-operative ADL statuses, only MGMT promoter methylation was found to be significantly associated with longer overall survival time in grade III (p = 0.024) and IV patients (p = 0.006). CONCLUSIONS:The incidences of MGMT promoter methylation and IDH1 mutation were found to be comparable to globally reported rates, but those of 1p19q co-deletion and ATRX loss seemed to be lower in our cohort. MGMT promoter methylation was associated with increased overall survival in our cohort and might serve as favorable prognostic factor.

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