Aerobic Exercise Reduces Aortic Pyroptosis By Inhibiting AGEs To Improve Oxidative Stress In Apoe-/-Mice

PURPOSE: Previous studies show that long-term hyperglycemia could exacerbate hypercholesterolemia induced atherosclerosis, which was alleviated by aerobic exercise. But the underline mechanism still needs further investigation. This work aims to explore the mechanism by which aerobic exercise can improve AGEs-mediated protection against atherosclerosis. METHODS: ApoE-/- (n = 45) male mice were provided a high-fat diet containing 1.25% cholesterol and randomly divided into diabetes control group (DC), diabetes mellitus group (DM)with high glucose model by STZ injection and diabetes exercise group (DE). The DE group of mice ran on a treadmill for 8 weeks (5 days/week, 40-60 minutes/day, 15 meters/minute). The levels of plasma glucose, serum insulin resistance, AGEs and ROS in aortic root were measured. The expressions of NLRP3, GSDMD, Caspase-1, IL-18 and IL-1β were detected by western blotting to evaluate the pyroptosis of aortic tissue. RESULTS: Compared with DC group, the fasting blood glucose, IR and AGEs in DM group were significantly increased (6.15 ± 0.41 vs 12.46 ± 0.98 mmol/L,23.10 ± 8.35 vs 176.57 ± 53.22,626.00 ± 25.10 vs 874.40 ± 11.45 pg/mL); as well as ROS and TUNEL index in aortic tissue (17.30 ± 3.56 vs 29.19 ± 4.03%,5.75 ± 1.18vs11.24 ± 3.61%), and pyroptosis related proteins NLRP3,Caspase-1,GSDMD,IL-18,IL-1β (3.31 ± 0.46 vs 5.90 ± 1.22,3.44 ± 1.14 vs 5.23 ± 0.73,1.49 ± 0.31 vs 2.14 ± 0.35,2.00 ± 0.51 vs 3.36 ± 1.05,3.22 ± 1.25 vs 6.68 ± 3.32). After training, all of indicators have been improved in DE group, characterized as fasting blood glucose, IR ,AGEs, ROS and TUNEL index in aortic tissue, the expressions of NLRP3,Caspase-1,GSDMD,IL-18,IL-1β (12.46 ± 0.98 vs 10.00 ± 0.57 mmol/L,176.57 ± 53.22 vs 58.03 ± 24.42,874.40 ± 11.45 vs 653.10 ± 8.84 pg/mL,29.19 ± 4.03 vs 18.94 ± 2.99%, 11.24 ± 3.61 vs 4.02 ± 1.01%,5.90 ± 1.22 vs 3.59 ± 0.81,5.23 ± 0.73 vs 3.09 ± 1.72,2.14 ± 0.35 vs 1.57 ± 0.36,3.36 ± 1.05 vs 2.39 ± 0.42,6.68 ± 3.32 vs 3.41 ± 1.10) (P < 0.05). CONCLUSIONS:AGEs might lead to the enhancement of oxidative stress response and aggravation of pyroptosis. Aerobic exercise significantly alleviates oxidative stress responses in the aortic tissue by improving hyperglycemia-induced AGEs, which makes a contribute to pyroptosis. Supported by: This work was supported by the Higher Education Institutions in Jiangsu Province (24KJA310002),Youth Project of National Natural Science Foundation of China(32000839),The Innovation and Entrepreneurship Training Program for Undergraduates of Jiangsu Province of China (202310330009).