Aerobic exercise improves BK_Ca channel-mediated vasodilation in diabetic vascular smooth muscle via AMPK/Nrf2/HO-1 pathway

Aims This study aims to investigate the effect of aerobic exercise training on BKCa channel in diabetic vascular smooth muscle and explore the underlying mechanism.Methods Control m/m mice and diabetic db/db mice were randomly assigned to sedentary groups (W and D) and exercise training groups (WE and DE). Mice in exercise groups underwent training sessions lasting for 12 weeks, with a speed of 12 m/min for 60 min, five times per week. The thoracic aorta was extracted isolated and examined for measurement of vascular structure, global levels of reactive oxygen species (ROS), vasodilation, and protein expression. Rat thoracic aorta vascular smooth muscle cells (USMCs) were cultured, and siRNA transfection was conducted to detect whether AMPK contributed to the regulation. ROS level and protein expression were measured.Results Compared with control mice, diabetic mice had a larger vascular medium thickness, impaired BKCa-mediated vasodilation, a higher level of ROS, and a lower expression of BKCa alpha, BKCa beta 1, Nrf2, p-Nrf2, p-Nrf2/Nrf2, HO-1, and p-AMPK/AMPK. Exercise training increased the expression of BKCa alpha, Nrf2, p-Nrf2, p-Nrf2/Nrf2, HO-1, and p-AMPK/AMPK. AMPK deletion led to lower ROS levels and expression of BKCa alpha, beta 1, Nrf2, and HO-1 in USMCs cultured in high glucose conditions.Conclusions BKCa channel protein expression reduction in VSMCs contributes to vasodilation and vascular remodeling dysfunction in diabetes mellitus. Aerobic exercise can promote the expression of BKCa channel and improve BKCa-mediated vascular dysfunction in diabetic VSMCs through AMPK/Nrf2/HO-1 signaling pathway.