Effect of metformin in a novel experimental model of peripheral artery disease.

IF 7.7 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Smriti Murali Krishna, Joseph Moxon, Ann-Katrin Kraeuter, Jonathan Golledge
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引用次数: 0

Abstract

Limited drug therapies for peripheral artery disease (PAD)-related walking impairment exist. There has been a recent interest in repurposing the diabetes medication metformin to treat PAD. Animal studies designed to develop new PAD drug therapies have mainly used a model of temporary hind limb ischaemia (HLI). The aim of this study was to test whether metformin improved blood supply and ambulation in a novel mouse model with ongoing HLI. Stable HLI was created in apolipoprotein E-deficient mice by a two-stage surgical procedure. Five days after HLI was induced, mice were randomly allocated to receive metformin (n = 16; 300 mg/kg/day) or vehicle control (n = 15) by oral gavage for four weeks. The primary outcome was hind limb blood supply assessed by laser Doppler. Other outcomes included treadmill performance and molecular changes in the ischaemic limb. Metformin improved hind limb blood supply (P<0.001), but not physical performance, associated with increased phosphorylation of 5' adenosine monophosphate-activated protein kinase and endothelial nitric oxide synthase (P<0.05), reduced expression of thioredoxin interacting protein (P<0.05) and increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (P<0.05) in the ischaemic muscles and increased circulating nitric oxide levels (P<0.05). Metformin improved blood supply in a novel model of limb ischaemia associated with molecular changes previously linked with promoting angiogenesis, but these changes did not translate to improved physical performance. The findings suggest that laser Doppler hind limb blood supply may not be an ideal outcome measure to gauge the success of a drug in patients with PAD-related walking impairment.

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二甲双胍对外周动脉疾病新实验模型的影响。
外周动脉疾病(PAD)相关行走障碍的药物治疗有限。最近有研究将糖尿病药物二甲双胍重新用于治疗外周动脉疾病。旨在开发新的PAD药物治疗的动物研究主要采用暂时性后肢缺血(HLI)模型。本研究的目的是测试二甲双胍是否能改善持续HLI的新型小鼠模型的血液供应和活动。在载脂蛋白E缺乏小鼠中,通过两阶段的外科手术建立了稳定的HLI。HLI诱导5天后,随机分配小鼠接受二甲双胍治疗(n=16;300mg/kg/天)或对照组(n=15)灌胃,持续4周。主要观察指标为激光多普勒评价后肢血供。其他结果包括跑步机表现和缺血肢体的分子变化。二甲双胍改善后肢血供(p
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来源期刊
Clinical science
Clinical science 医学-医学:研究与实验
CiteScore
11.40
自引率
0.00%
发文量
189
审稿时长
4-8 weeks
期刊介绍: Translating molecular bioscience and experimental research into medical insights, Clinical Science offers multi-disciplinary coverage and clinical perspectives to advance human health. Its international Editorial Board is charged with selecting peer-reviewed original papers of the highest scientific merit covering the broad spectrum of biomedical specialities including, although not exclusively: Cardiovascular system Cerebrovascular system Gastrointestinal tract and liver Genomic medicine Infection and immunity Inflammation Oncology Metabolism Endocrinology and nutrition Nephrology Circulation Respiratory system Vascular biology Molecular pathology.
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