Acid Sphingomyelinase Down-regulation Alleviates Vascular Endothelial Insulin Resistance in Diabetic Rats.
Acid Sphingomyelinase Down-regulation Alleviates Vascular Endothelial Insulin Resistance in Diabetic Rats.
复制标题
酸性鞘磷脂酶下调可减轻糖尿病大鼠的血管内皮胰岛素抵抗。
DOI：
10.1111/bcpt.13073
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发表时间：
2018
影响因子：
3.1
通讯作者：
Ming Xu
中科院分区：
文献类型：
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作者：
Xin Li;Shi-Jie Jin;Jie Su;Xiao-Xue Li;Ming Xu
2型糖尿病患者血管内皮细胞胰岛素抵抗与心血管疾病的发生有关。酸性鞘磷脂酶（ASM）是一种可溶性糖蛋白，在心血管和代谢性疾病等多种疾病的发生发展中起着重要作用。然而，它仍然是未知的，如果ASM调节2型糖尿病血管内皮细胞的胰岛素抵抗。在用棕榈酸（PA）处理的大鼠主动脉内皮细胞（RAEC）中使用ASM下调基因沉默和选择性抑制剂阿米替林，棕榈酸是一种常见的饱和游离脂肪酸，被认为是胰岛素抵抗的主要原因。结果表明，ASM下调增加葡萄糖摄取和葡萄糖转运蛋白-4（Glut 4）表达，并通过神经酰胺逆转pIRS-1-ser 307和AKT-ser 473的磷酸化，从而导致PA诱导的RAEC中内皮型一氧化氮合酶（eNOS）和一氧化氮的产生减少。我们进一步发现，ASM下调阻断了Nox 2和Nox 4依赖的超氧化物（O2−·）的产生，而O2−·在PA刺激过程中调节RAEC的葡萄糖代谢。在体内，阿米替林减轻了乙酰胆碱的血管舒张反应，并恢复了注射链脲佐菌素后高脂饮食大鼠主动脉内皮中神经酰胺、Nox 2和Nox 4的水平。总之，这些结果表明，ASM下调可以改善内皮胰岛素抵抗，这归因于抑制RAEC中的氧化还原信号传导。因此，这些数据支持ASM是一种有前途的临床生物标志物和糖尿病血管并发症的潜在治疗靶点的想法。
Insulin resistance in endothelial cells contributes to the development of cardiovascular disease in patients with type 2 diabetes. Acid sphingomyelinase (ASM) is a soluble glycoprotein which plays a vital role in the development and progression of various diseases such as cardiovascular and metabolic diseases. However, it remains unknown if ASM regulates insulin resistance in vascular endothelial cells in type 2 diabetes. ASM down‐regulation with gene silencing and selective inhibitor amitriptyline was used in the rat aortic endothelial cells (RAECs) treated with palmitic acid (PA), a common saturated free fatty acid, which is thought to be the major cause of insulin resistance. It was shown that ASM down‐regulation increased glucose uptake and glucose transporter‐4 (Glut4) expression and reversed the phosphorylation of pIRS‐1‐ser307 and AKT‐ser473 via ceramide, consequently resulting in the decrease of the production of endothelial nitric oxide synthase (eNOS) and nitric oxide in PA‐induced RAECs. We further found that ASM down‐regulation blocked the Nox2‐ and Nox4‐dependent superoxide (O2−·) generation, which regulated glucose metabolism in RAECs during PA stimulation.In vivo, amitriptyline relieved the vasodilatory response to acetylcholine and restored the level of ceramide, Nox2 and Nox4 in the aorta endothelium of high‐fat diet‐fed rats following an injection of streptozotocin. Taken together, these results suggest that ASM down‐regulation can improve endothelial insulin resistance which is attributed to inhibiting redox signalling in RAECs. Thus, these data support the idea that ASM is a promising clinical biomarker and potential therapeutic target for diabetic vascular complication.