Protective Effect of Irisin on Atherosclerosis via Suppressing Oxidized Low Density Lipoprotein Induced Vascular Inflammation and Endothelial Dysfunction

Irisin, a newly discovered myokine, is considered as a promising candidate for the treatment of metabolic disturbances and cardiovascular diseases. In the present study, we used two animal models, apolipoprotein E-deficient mice fed on a high-cholesterol diet and a mouse carotid partial ligation model to test the anti-atherosclerotic effect of irisin. Irisin treatment (0.5 μg/g body weight/day) significantly reduced the severity of aortic atherosclerosis in apolipoprotein E-deficient mice fed on a high-cholesterol diet and suppressed carotid neointima formation in a carotid partial ligation model. It was associated with decreased inflammation and cell apoptosis in aortic tissues. In addition, in a cell culture model, irisin restored ox-LDL-induced human umbilical vein endothelial cell dysfunction by reducing the levels of inflammatory genes via inhibiting the reactive oxygen species (ROS)/ p38 MAPK/ NF-κB signaling pathway activation and inhibiting cell apoptosis via up-regulating Bcl-2 and down-regulating Bax and caspase-3 expression. Our study demonstrated that irisin significantly reduced atherosclerosis in apolipoprotein E-deficient mice via suppressing ox-LDL-induced cell inflammation and apoptosis, which might have a direct therapeutic effect on atherosclerotic diseases.鸢尾素（Irisin）是一种新近发现的肌因子，被认为是治疗代谢紊乱与心血管疾病的极具潜力的候选药物。本研究采用两种动物模型——喂食高胆固醇饮食的载脂蛋白E缺陷小鼠，以及颈动脉部分结扎小鼠模型，以验证鸢尾素的抗动脉粥样硬化作用。实验结果显示，以0.5 μg/g体重/天的剂量给予鸢尾素治疗，可显著降低高胆固醇饮食喂养的载脂蛋白E缺陷小鼠的主动脉粥样硬化病变程度，并抑制颈动脉部分结扎模型中的颈动脉新生内膜形成。该保护效应与主动脉组织内炎症反应减轻、细胞凋亡受抑密切相关。此外，在细胞培养模型中，鸢尾素可通过抑制活性氧（ROS）/p38丝裂原活化蛋白激酶（MAPK）/核因子κB（NF-κB）信号通路的激活，降低炎症基因的表达水平，从而逆转氧化低密度脂蛋白（ox-LDL）诱导的人脐静脉内皮细胞功能障碍；同时还可通过上调B细胞淋巴瘤/白血病-2（Bcl-2）的表达、下调Bcl-2相关X蛋白（Bax）与半胱氨酸天冬氨酸蛋白酶-3（caspase-3）的表达，抑制细胞凋亡。本研究证实，鸢尾素可通过抑制ox-LDL诱导的细胞炎症反应与细胞凋亡，显著减轻载脂蛋白E缺陷小鼠的动脉粥样硬化病变，这或许可为动脉粥样硬化性疾病发挥直接治疗作用。