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

Abstract

Aims: This study aims to investigate the effect of aerobic exercise training on BK_Ca 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 BK_Ca-mediated vasodilation, a higher level of ROS, and a lower expression of BK_Ca α, BK_Ca β1, Nrf2, p-Nrf2, p-Nrf2/Nrf2, HO-1, and p-AMPK/AMPK. Exercise training increased the expression of BK_Ca α, Nrf2, p-Nrf2, p-Nrf2/Nrf2, HO-1, and p-AMPK/AMPK. AMPK deletion led to lower ROS levels and expression of BK_Ca α, β1, Nrf2, and HO-1 in USMCs cultured in high glucose conditions.

Conclusions: BK_Ca channel protein expression reduction in VSMCs contributes to vasodilation and vascular remodeling dysfunction in diabetes mellitus. Aerobic exercise can promote the expression of BK_Ca channel and improve BK_Ca-mediated vascular dysfunction in diabetic VSMCs through AMPK/Nrf2/HO-1 signaling pathway.

Keywords: AMPK/Nrf2 pathway; Aerobic exercise; BKCa channel; Diabetes mellitus; Vascular smooth muscle.