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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 α, BKCa β1, Nrf2, p-Nrf2, p-Nrf2/Nrf2, HO-1, and p-AMPK/AMPK. Exercise training increased the expression of BKCa α, Nrf2, p-Nrf2, p-Nrf2/Nrf2, HO-1, and p-AMPK/AMPK. AMPK deletion led to lower ROS levels and expression of BKCa α, β1, 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. [ABSTRACT FROM AUTHOR]

• •OH could be rapidly generated from Fe2+/EDTA system (O 2 atmosphere). • Fe2+-EDTA activate O 2 to induce H 2 O 2 in-situ via direct 2-electron transformation. • EDTA tune the production pathways of radical or intermediate in Fenton system. • The dual effect of •OH and O 2 •− was revealed in Fe3+/EDTA/H 2 O 2 system. The Fenton system was a generation system of reactive oxygen species via the chain reactions, which employed H 2 O 2 and O 2 as radical precursors and Fe2+/Fe3+ as electron-donor/acceptor for triggering or terminating the generation of radicals. Recent work mainly emphasized the Fe2+- activated H 2 O 2 and the application of in-situ generated •OH, while neglecting other side-reactions. In this work, EDTA (Ethylene diamine tetraacetic acid) was employed as a chelating agent of iron ions, which simultaneously changed the redox property of coordinated iron. The Fe2+-EDTA complexes in the presence of dissolved oxygen enabled the two-electron transfer from Fe2+ to O 2 and the in-situ production of H 2 O 2 , which further activate H 2 O 2 for yielding •OH. Meanwhile, coordinated Fe3+ exhibited non-negligible reactivity toward H 2 O 2 , which was higher than that of free Fe3+ in the traditional Fenton system. The complexation of EDTA with Fe3+ could enhance the Fe2+ generation reaction by the H 2 O 2 , accompanied by the O 2 •− formation. The enhancement of O 2 •− formation and Fe2+-EDTA regeneration induced the subsequent H 2 O 2 activation by Fe2+-EDTA, thus accelerating the Fe3+-EDTA/Fe2+-EDTA cycle for simultaneously producing O 2 •− and •OH. To sum up, the EDTA-chelated Fenton system extended the applicable pH range to circumneutral/alkaline level and tuned the redox property of coordinated iron for diversifying the •OH production routes. The research reinterpreted the chain reactions in the Fenton system, revealing another way to enhance the radical production or other property of the Fenton/Fenton-like system. [Display omitted] [ABSTRACT FROM AUTHOR]