Targeting endothelial thioredoxin-interacting protein (TXNIP) protects from metabolic disorder-related impairment of vascular function and post-ischemic revascularisation
Targeting endothelial thioredoxin-interacting protein (TXNIP) protects from metabolic disorder-related impairment of vascular function and post-ischemic revascularisation
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DOI：
10.1007/s10456-019-09704-x
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发表时间：
2020-05-01
期刊：
影响因子：
9.8
通讯作者：
Nivet-Antoine, Valerie
中科院分区：
文献类型：
--
作者：
Domingues, Alison;Boisson-Vidal, Catherine;Nivet-Antoine, Valerie
虽然硫氧还蛋白相互作用蛋白（TXNIP）参与多种生物功能，但内皮TXNIP在内皮和血管功能或缺血后血管重建方面的作用尚未明确。我们假设用siRNA或Cre-LoxP系统抑制内皮TXNIP可能参与保护高脂肪、高蛋白、低碳水化合物（HFHPLC）饮食诱导的氧化应激和内皮功能障碍，从而导致体内血管损伤和血管重建受损。方法和结果为了研究内皮细胞中TXNIP的作用，采用抗TXNIP siRNA处理或Cre-LoxP系统删除内皮细胞中的TXNIP基因。小鼠模型被喂食HFHPLC饮食，已知会引起代谢紊乱。内皮TXNIP靶向导致对代谢紊乱相关的内皮氧化应激和内皮功能障碍的保护。这种保护作用减轻了代谢性疾病和代谢性疾病相关血管功能障碍引起的介质细胞损失，通过主动脉反应性和扩张性进行评估。在主动脉环培养中，代谢紊乱会损害血管发芽，这种改变可以通过内皮细胞TXNIP的缺失得到缓解。饲喂高氟高效液相色谱的小鼠在缺血时表现出缺血后血管生成缺陷和后肢缺血血流恢复受损。然而，减少内皮TXNIP可挽救代谢紊乱相关的缺血引起的血运重建损伤。综上所述，这些结果表明，在代谢紊乱中靶向内皮TXNIP对于维持内皮功能、血管功能和改善缺血诱导的血运重建至关重要，TXNIP可能成为治疗代谢紊乱相关血管并发症的潜在治疗靶点。
Introduction Although thioredoxin-interacting protein (TXNIP) is involved in a variety of biological functions, the contribution of endothelial TXNIP has not been well-defined in regards to endothelial and vascular function or in post-ischemic revascularisation. We postulated that inhibition of endothelial TXNIP with siRNA or in a Cre-LoxP system could be involved in protection from high fat, high protein, low carbohydrate (HFHPLC) diet-induced oxidative stress and endothelial dysfunction, leading to vascular damage and impaired revascularisation in vivo. Methods and results To investigate the role of endothelial TXNIP, the TXNIP gene was deleted in endothelial cells using anti-TXNIP siRNA treatment or the Cre-LoxP system. Murine models were fed a HFHPLC diet, known to induce metabolic disorders. Endothelial TXNIP targeting resulted in protection against metabolic disorder-related endothelial oxidative stress and endothelial dysfunction. This protective effect mitigates media cell loss induced by metabolic disorders and hampered metabolic disorder-related vascular dysfunction assessed by aortic reactivity and distensibility. In aortic ring cultures, metabolic disorders impaired vessel sprouting and this alteration was alleviated by deletion of endothelial TXNIP. When subjected to ischemia, mice fed a HFHPLC diet exhibited defective post-ischemic angiogenesis and impaired blood flow recovery in hind limb ischemia. However, reducing endothelial TXNIP rescued metabolic disorder-related impairment of ischemia-induced revascularisation. Conclusion Collectively, these results show that targeting endothelial TXNIP in metabolic disorders is essential to maintaining endothelial function, vascular function and improving ischemia-induced revascularisation, making TXNIP a potential therapeutic target for therapy of vascular complications related to metabolic disorders.