Reduced endothelial thioredoxin-interacting protein protects arteries from damage induced by metabolic stress in vivo
Reduced endothelial thioredoxin-interacting protein protects arteries from damage induced by metabolic stress in vivo
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DOI：
10.1096/fj.201700856rrr
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发表时间：
2018-06-01
期刊：
影响因子：
4.8
通讯作者：
Nivet-Antoine, Valerie
中科院分区：
文献类型：
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作者：
Bedarida, Tatiana;Domingues, Alison;Nivet-Antoine, Valerie
虽然硫氧还蛋白相互作用蛋白（TXNIP）参与了多种生物学功能，但内皮TXNIP的作用尚未得到很好的定义。为了研究TXNIP的内皮功能，我们在Cdh 5-cre背景上产生了TXNIP敲除小鼠（TXNIP fl/fl cdh 5（cre））。对照（TXNIPfl/fl）和TXNIPfl/fl cdh 5（cre）小鼠喂食高蛋白-低碳水化合物（HP-LC）饮食3个月以诱导代谢应激。我们发现，TXNIPfl/fl和TXNIPfl/fl cdh 5（cre）小鼠在HP-LC饮食中显示出葡萄糖耐量受损和血脂异常，从而使诱导的代谢应激具体化。我们评估了这种代谢应激对内皮TXNIP表达减少的小鼠动脉结构和功能的影响。HP-LC饮食的TXNIPf 1/f1 cdh 5（cre）小鼠比HP-LC饮食的同窝小鼠表现出更少的内皮功能障碍。这些小鼠的主动脉中膜细胞含量减少，主动脉扩张性受损，纤溶酶原激活物抑制剂1分泌增加。这种保护作用伴随着较低的氧化应激和较低的炎症，伴随着NLRP 3炎性体表达的减少，导致裂解的IL-1 β的减少。我们还显示了TXNIP在炎症中的主要作用与敲低模型，使用TXNIP特异性，小干扰RNA包括在lipoplex。这些发现表明内皮TXNIP在代谢应激诱导的动脉损伤中的关键作用，使内皮TXNIP成为潜在的治疗靶点。
Although thioredoxin-interacting protein (TXNIP) is involved in a variety of biologic functions, the contribution of endothelial TXNIP has not been well defined. To investigate the endothelial function of TXNIP, we generated a TXNIP knockout mouse on the Cdh5-cre background (TXNIPfl/fl cdh5(cre)). Control (TXNIPfl/fl) and TXNIPfl/fl cdh5(cre) mice were fed a high protein-low carbohydrate (HP-LC) diet for 3 mo to induce metabolic stress. We found that TXNIPfl/fl and TXNIPfl/fl cdh5(cre) mice on an HP-LC diet displayed impaired glucose tolerance and dyslipidemia concretizing the metabolic stress induced. We evaluated the impact of this metabolic stress on mice with reduced endothelial TXNIP expression with regard to arterial structure and function. TXNIPfl/fl cdh5(cre) mice on an HP-LC diet exhibited less endothelial dysfunction than littermate mice on an HP-LC diet. These mice were protected from decreased aortic medial cell content, impaired aortic distensibility, and increased plasminogen activator inhibitor 1 secretion. This protective effect came with lower oxidative stress and lower inflammation, with a reduced NLRP3 inflammasome expression, leading to a decrease in cleaved IL-1 beta. We also show the major role of TXNIP in inflammation with a knockdown model, using a TXNIP-specific, small interfering RNA included in a lipoplex. These findings demonstrate a key role for endothelial TXNIP in arterial impairments induced by metabolic stress, making endothelial TXNIP a potential therapeutic target.