Graduate School of Science, Nagoya City University, Nagoya, Japan.
National Institute of Occupational Safety and Health, Tokyo, Japan.
FASEB J. 2021 Jul;35(7):e21698. doi: 10.1096/fj.202002790RR.
Regular exercise maintains arterial endothelial cell homeostasis and protects the arteries from vascular disease, such as peripheral artery disease and atherosclerosis. Autophagy, which is a cellular process that degrades misfolded or aggregate proteins and damaged organelles, plays an important role in maintaining organ and cellular homeostasis. However, it is unknown whether regular exercise stimulates autophagy in aorta endothelial cells of mice prone to atherosclerosis independently of their circulating lipid profile. Here, we observed that 16 weeks of voluntary exercise reduced high-fat diet-induced atherosclerotic plaque formation in the aortic root of ApoE deficient mice, and that this protection occurred without changes in circulating triglycerides, total cholesterol, and lipoproteins. Immunofluorescence analysis indicated that voluntary exercise increased levels of the autophagy protein LC3 in aortic endothelial cells. Interestingly, human umbilical vein endothelial cells (HUVECs) exposed to serum from voluntarily exercised mice displayed significantly increased LC3-I and LC3-II protein levels. Analysis of circulating cytokines demonstrated that voluntary exercise caused changes directly relevant to IL-1 signaling (ie, decreased interleukin-1 receptor antagonist [IL-1ra] while also increasing IL-1α). HUVECs exposed to IL-1α and IL-1β recombinant protein significantly increased LC3 mRNA expression, LC3-I and LC3-II protein levels, and autophagy flux. Collectively, these results suggest that regular exercise protects arteries from ApoE deficient mice against atherosclerosis at least in part by stimulating endothelial cell autophagy via enhanced IL-1 signaling.
规律运动维持动脉内皮细胞的内稳态，并保护动脉免受血管疾病的侵害，如外周动脉疾病和动脉粥样硬化。自噬是一种细胞过程，可降解错误折叠或聚集的蛋白质和受损的细胞器，在维持器官和细胞内稳态方面发挥着重要作用。然而，目前尚不清楚规律运动是否可以独立于循环脂质谱，刺激易患动脉粥样硬化的小鼠主动脉内皮细胞中的自噬。在这里，我们观察到 16 周的自愿运动减少了载脂蛋白 E 缺陷小鼠主动脉根部的高脂饮食诱导的动脉粥样硬化斑块形成，而这种保护作用并没有改变循环甘油三酯、总胆固醇和脂蛋白。免疫荧光分析表明，自愿运动增加了主动脉内皮细胞中自噬蛋白 LC3 的水平。有趣的是，暴露于自愿运动小鼠血清中的人脐静脉内皮细胞 (HUVECs) 显示 LC3-I 和 LC3-II 蛋白水平显著增加。对循环细胞因子的分析表明，自愿运动导致与 IL-1 信号直接相关的变化（即，白细胞介素-1 受体拮抗剂 [IL-1ra] 减少，同时白细胞介素-1α [IL-1α] 增加）。暴露于 IL-1α 和 IL-1β 重组蛋白的 HUVECs 显著增加了 LC3 mRNA 表达、LC3-I 和 LC3-II 蛋白水平以及自噬通量。总的来说，这些结果表明，规律运动通过增强 IL-1 信号至少部分地通过刺激内皮细胞自噬来保护 ApoE 缺陷小鼠的动脉免受动脉粥样硬化的侵害。
