PDF(Pubmed)
Abstract：
UNASSIGNED: Metformin treatment attenuates experimental abdominal aortic aneurysm (AAA) formation, as well as reduces clinical AAA diameter enlargement in patients with diabetes. The mechanisms of metformin-mediated aneurysm suppression, and its efficacy in suppressing established experimental aneurysms, remain uncertain.
UNASSIGNED: Experimental AAAs were created in male C57BL/6J mice via intra-aortic infusion of porcine pancreatic elastase. Metformin alone (250 mg/kg), or metformin combined with the 5\' AMP-activated protein kinase (AMPK) antagonist Compound C (10 mg/kg), were administered to respective mouse cohorts daily beginning 4 days following AAA induction. Further AAA cohorts received either the AMPK agonist AICA riboside (500 mg/kg) as positive, or vehicle (saline) as negative, controls. AAA progression in all groups was assessed via serial in vivo ultrasonography and histopathology at sacrifice. Cytokine-producing T cells and myeloid cellularity were determined by flow cytometric analyses.
UNASSIGNED: Metformin limited established experimental AAA progression at 3 (-85%) and 10 (-68%) days following treatment initiation compared with saline control. Concurrent Compound C treatment reduced this effect by approximately 50%. In metformin-treated mice, reduced AAA progression was associated with relative elastin preservation, smooth muscle cell preservation, and reduced mural leukocyte infiltration and neoangiogenesis compared with vehicle control group. Metformin also resulted in reduced interferon-γ-, but not interleukin-10 or -17, producing splenic T cells in aneurysmal mice. Additionally, metformin therapy increased circulating and splenic inflammatory monocytes (CD11b+Ly-6Chigh), but not neutrophils (CD11b+Ly-6G+), with no effect on respective bone marrow cell populations.
UNASSIGNED: Metformin treatment suppresses existing experimental AAA progression in part via AMPK agonist activity, limiting interferon-γ-producing T cell differentiation while enhancing circulating and splenic inflammatory monocyte retention.
UNASSIGNED: Experimental AAAs were created in male C57BL/6J mice via intra-aortic infusion of porcine pancreatic elastase. Metformin alone (250 mg/kg), or metformin combined with the 5\' AMP-activated protein kinase (AMPK) antagonist Compound C (10 mg/kg), were administered to respective mouse cohorts daily beginning 4 days following AAA induction. Further AAA cohorts received either the AMPK agonist AICA riboside (500 mg/kg) as positive, or vehicle (saline) as negative, controls. AAA progression in all groups was assessed via serial in vivo ultrasonography and histopathology at sacrifice. Cytokine-producing T cells and myeloid cellularity were determined by flow cytometric analyses.
UNASSIGNED: Metformin limited established experimental AAA progression at 3 (-85%) and 10 (-68%) days following treatment initiation compared with saline control. Concurrent Compound C treatment reduced this effect by approximately 50%. In metformin-treated mice, reduced AAA progression was associated with relative elastin preservation, smooth muscle cell preservation, and reduced mural leukocyte infiltration and neoangiogenesis compared with vehicle control group. Metformin also resulted in reduced interferon-γ-, but not interleukin-10 or -17, producing splenic T cells in aneurysmal mice. Additionally, metformin therapy increased circulating and splenic inflammatory monocytes (CD11b+Ly-6Chigh), but not neutrophils (CD11b+Ly-6G+), with no effect on respective bone marrow cell populations.
UNASSIGNED: Metformin treatment suppresses existing experimental AAA progression in part via AMPK agonist activity, limiting interferon-γ-producing T cell differentiation while enhancing circulating and splenic inflammatory monocyte retention.
摘要：
■二甲双胍治疗可减弱实验性腹主动脉瘤（AAA）的形成，以及减少糖尿病患者的临床AAA直径扩大。二甲双胍介导的动脉瘤抑制机制,以及它在抑制已建立的实验性动脉瘤方面的功效，仍然不确定。
■通过主动脉内输注猪胰弹性蛋白酶在雄性C57BL/6J小鼠中产生实验性AAAs。单独使用二甲双胍（250mg/kg），或二甲双胍联合5'AMP活化蛋白激酶（AMPK）拮抗剂化合物C（10mg/kg），在AAA诱导后4天开始,每天给予相应的小鼠队列。其他AAA队列接受AMPK激动剂AICA核苷（500mg/kg）为阳性，或载体（盐水）为阴性，controls.通过连续体内超声检查和处死时的组织病理学评估所有组的AAA进展。通过流式细胞术分析确定产生细胞因子的T细胞和髓样细胞数量。
■与盐水对照相比，二甲双胍在治疗开始后3天（-85％）和10天（-68％）限制了已建立的实验性AAA进展。同时的化合物C处理使这种效果降低了大约50%。在二甲双胍治疗的小鼠中，AAA进展减少与相对弹性蛋白保存相关，平滑肌细胞保存，与载体对照组相比，壁白细胞浸润和新血管生成减少。二甲双胍还导致干扰素-γ-，但不是白细胞介素-10或-17，在动脉瘤小鼠中产生脾T细胞。此外,二甲双胍治疗增加循环和脾炎症单核细胞（CD11b+Ly-6Chigh），但不是中性粒细胞（CD11b+Ly-6G+），对各自的骨髓细胞群没有影响。
■二甲双胍治疗部分通过AMPK激动剂活性抑制现有的实验性AAA进展，限制产生干扰素γ的T细胞分化，同时增强循环和脾炎症单核细胞滞留。
■通过主动脉内输注猪胰弹性蛋白酶在雄性C57BL/6J小鼠中产生实验性AAAs。单独使用二甲双胍（250mg/kg），或二甲双胍联合5'AMP活化蛋白激酶（AMPK）拮抗剂化合物C（10mg/kg），在AAA诱导后4天开始,每天给予相应的小鼠队列。其他AAA队列接受AMPK激动剂AICA核苷（500mg/kg）为阳性，或载体（盐水）为阴性，controls.通过连续体内超声检查和处死时的组织病理学评估所有组的AAA进展。通过流式细胞术分析确定产生细胞因子的T细胞和髓样细胞数量。
■与盐水对照相比，二甲双胍在治疗开始后3天（-85％）和10天（-68％）限制了已建立的实验性AAA进展。同时的化合物C处理使这种效果降低了大约50%。在二甲双胍治疗的小鼠中，AAA进展减少与相对弹性蛋白保存相关，平滑肌细胞保存，与载体对照组相比，壁白细胞浸润和新血管生成减少。二甲双胍还导致干扰素-γ-，但不是白细胞介素-10或-17，在动脉瘤小鼠中产生脾T细胞。此外,二甲双胍治疗增加循环和脾炎症单核细胞（CD11b+Ly-6Chigh），但不是中性粒细胞（CD11b+Ly-6G+），对各自的骨髓细胞群没有影响。
■二甲双胍治疗部分通过AMPK激动剂活性抑制现有的实验性AAA进展，限制产生干扰素γ的T细胞分化，同时增强循环和脾炎症单核细胞滞留。
