Lu Junyan, Xiang Guangda, Liu Min, Mei Wen, Xiang Lin, Dong Jing
Department of Endocrinology, Wuhan General Hospital of Guangzhou Command, Wuluo Road 627, Wuhan 430070, Hubei Province, China.
Atherosclerosis. 2015 Dec;243(2):438-48. doi: 10.1016/j.atherosclerosis.2015.10.020. Epub 2015 Oct 19.
The circulating irisin increases energy expenditure and improves insulin resistance in mice and humans. The improvement of insulin resistance ameliorates atherosclerosis. Therefore, we hypothesized that irisin alleviates atherosclerosis in diabetes.
Endothelial function was measured by acetylcholine-induced endothelium-dependent vasodilation using aortic rings in apolipoprotein E-Null (apoE(-/-)) streptozotocin-induced diabetic mice. Atherosclerotic lesion was evaluated by plaque area and inflammatory response in aortas. In addition, the endothelium-protective effects of irisin were also further investigated in primary human umbilical vein endothelial cells (HUVECs) in vitro.
The in vivo experiments showed that irisin treatment significantly improved endothelial dysfunction, decreased endothelial apoptosis, and predominantly decreased atherosclerotic plaque area of both en face and cross sections when compared with normal saline-treated diabetic mice. Moreover, the infiltrating macrophages and T lymphocytes within plaque and the mRNA expression levels of inflammatory cytokines in aortas were also significantly reduced by irisin treatment in mice. The in vitro experiments revealed that irisin inhibited high glucose-induced apoptosis, oxidative stress and increased antioxidant enzymes expression in HUVECs, and pretreatment with LY294002, l-NAME, AMPK-siRNA or eNOS-siRNA, attenuated the protection of irisin on HUVECs apoptosis induced by high glucose. In addition, the in vivo and in vitro experiments showed that irisin increased the phosphorylation of AMPK, Akt and eNOS in aortas and cultured HUVECs.
The present study indicates that systemic administration of irisin may be protected against endothelial injury and ameliorated atherosclerosis in apoE(-/-) diabetic mice. The endothelium-protective action of irisin was through activation of AMPK-PI3K-Akt-eNOS signaling pathway. Irisin could be therapeutic for atherosclerotic vascular diseases in diabetes.
循环鸢尾素可增加小鼠和人类的能量消耗并改善胰岛素抵抗。胰岛素抵抗的改善可减轻动脉粥样硬化。因此，我们推测鸢尾素可减轻糖尿病中的动脉粥样硬化。
使用载脂蛋白E基因敲除（apoE(-/-)）链脲佐菌素诱导的糖尿病小鼠的主动脉环，通过乙酰胆碱诱导的内皮依赖性血管舒张来测量内皮功能。通过主动脉的斑块面积和炎症反应评估动脉粥样硬化病变。此外，还在体外原代人脐静脉内皮细胞（HUVECs）中进一步研究了鸢尾素的内皮保护作用。
体内实验表明，与生理盐水处理的糖尿病小鼠相比，鸢尾素治疗可显著改善内皮功能障碍，减少内皮细胞凋亡，并且主要减少正面和横截面的动脉粥样硬化斑块面积。此外，鸢尾素治疗还可显著降低小鼠斑块内浸润的巨噬细胞和T淋巴细胞以及主动脉中炎性细胞因子的mRNA表达水平。体外实验表明，鸢尾素可抑制高糖诱导的HUVECs凋亡、氧化应激并增加抗氧化酶表达，用LY294002、L-NAME、AMPK-siRNA或eNOS-siRNA预处理可减弱鸢尾素对高糖诱导的HUVECs凋亡的保护作用。此外，体内和体外实验均表明，鸢尾素可增加主动脉和培养的HUVECs中AMPK、Akt和eNOS的磷酸化。
本研究表明，全身性给予鸢尾素可能对apoE(-/-)糖尿病小鼠的内皮损伤具有保护作用，并可减轻动脉粥样硬化。鸢尾素的内皮保护作用是通过激活AMPK-PI3K-Akt-eNOS信号通路实现的。鸢尾素可能对糖尿病中的动脉粥样硬化性血管疾病具有治疗作用。
