Padilla Jaume, Thorne Pamela K, Martin Jeffrey S, Rector R Scott, Akter Sadia, Davis J Wade, Laughlin M Harold, Jenkins Nathan T
1 Nutrition and Exercise Physiology, University of Missouri, Columbia, MO 65211, USA.
2 Child Health, University of Missouri, Columbia, MO 65211, USA.
Exp Biol Med (Maywood). 2017 Mar;242(6):617-624. doi: 10.1177/1535370216689825. Epub 2017 Jan 23.
We examined the effects of metformin, a commonly used antidiabetic drug, on gene expression in multiple arteries. Specifically, transcriptional profiles of feed arteries and second branch order arterioles in the soleus, gastrocnemius, and diaphragm muscles as well as aortic endothelial scrapes were examined from obese insulin-resistant Otsuka Long-Evans Tokushima Fatty rats treated with ( n = 9) or without ( n = 10) metformin from 20 to 32 weeks of age. Metformin-treated rats exhibited a reduction in body weight, adiposity, and HbA1c ( P < 0.05). The greatest number of differentially expressed genes (FDR < 15%) between those treated with and without metformin was found in the red gastrocnemius 2a arterioles (93 genes), followed by the diaphragm 2a arterioles (62 genes), and soleus 2a arterioles (15 genes). We also found that two genes were differentially expressed in aortic endothelial cells (LETMD1 and HMGCS2, both downregulated), one gene in the gastrocnemius feed artery (BLNK, downregulated), and no genes in the soleus and diaphragm feed arteries and white gastrocnemius 2a arterioles. No single gene was altered by metformin across all vessels examined. This study provides evidence that metformin treatment produces distinct gene expression effects throughout the arterial tree in a rat model of obesity and insulin resistance. Genes whose expression was modulated with metformin do not appear to have a clear connection with its known mechanisms of action. These findings support the notion that vascular gene regulation in response to oral pharmacological therapy, such as metformin, is vessel specific. Impact statement This study provides evidence that metformin treatment produces artery-specific gene expression effects. The genes whose expression was modulated with metformin do not appear to have a clear connection with its known mechanisms of action.
我们研究了常用抗糖尿病药物二甲双胍对多条动脉中基因表达的影响。具体而言，我们检测了来自20至32周龄用（n = 9）或未用（n = 10）二甲双胍治疗的肥胖胰岛素抵抗型大冢长-艾氏-德岛肥胖大鼠的比目鱼肌、腓肠肌和膈肌的供血动脉及二级分支小动脉以及主动脉内皮刮片的转录谱。接受二甲双胍治疗的大鼠体重、肥胖程度和糖化血红蛋白水平均有所降低（P < 0.05）。在用和未用二甲双胍治疗的大鼠之间，差异表达基因数量最多（错误发现率< 15%）的是红色腓肠肌2a小动脉（93个基因），其次是膈肌2a小动脉（62个基因），以及比目鱼肌2a小动脉（15个基因）。我们还发现，有两个基因在主动脉内皮细胞中差异表达（LETMD1和HMGCS２，均下调），一个基因在腓肠肌供血动脉中差异表达（BLNK，下调），而在比目鱼肌和膈肌供血动脉以及白色腓肠肌2a小动脉中没有基因差异表达。在所有检测的血管中，没有一个基因受二甲双胍影响而发生单一改变。本研究提供了证据表明，在肥胖和胰岛素抵抗大鼠模型中，二甲双胍治疗在整个动脉树中产生了独特的基因表达效应。其表达受二甲双胍调节的基因似乎与其已知作用机制没有明确关联。这些发现支持了这样一种观点，即口服药理治疗（如二甲双胍）引起的血管基因调控具有血管特异性。影响声明 本研究提供了证据表明，二甲双胍治疗产生了动脉特异性基因表达效应。其表达受二甲双胍调节的基因似乎与其已知作用机制没有明确关联。
