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Empagliflozin suppresses mitochondrial reactive oxygen species generation and mitigates the inducibility of atrial fibrillation in diabetic rats

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Title: Empagliflozin suppresses mitochondrial reactive oxygen species generation and mitigates the inducibility of atrial fibrillation in diabetic rats
Authors: Koizumi, Takuya Browse this author
Watanabe, Masaya Browse this author →KAKEN DB
Yokota, Takashi Browse this author
Tsuda, Masumi Browse this author
Handa, Haruka Browse this author
Koya, Jiro Browse this author
Nishino, Kotaro Browse this author
Tatsuta, Daishiro Browse this author
Natsui, Hiroyuki Browse this author
Kadosaka, Takahide Browse this author
Koya, Taro Browse this author
Nakao, Motoki Browse this author
Hagiwara, Hikaru Browse this author
Kamada, Rui Browse this author
Temma, Taro Browse this author
Tanaka, Shinya Browse this author
Anzai, Toshihisa Browse this author →KAKEN DB
Keywords: empagliflozin
reactive oxygen species
SGLT2 inhibitor
Issue Date: 6-Feb-2023
Publisher: Frontiers Media
Journal Title: Frontiers in Cardiovascular Medicine
Volume: 10
Start Page: 1005408
Publisher DOI: 10.3389/fcvm.2023.1005408
Abstract: IntroductionRecent studies have demonstrated that sodium-glucose co-transporter-2 inhibitors (SGLT2-i) reduce the risk of atrial fibrillation (AF) in patients with diabetes mellitus (DM), in which oxidative stress due to increased reactive oxygen species (ROS) contributes to the pathogenesis of AF. We aimed to further investigate this, and examine whether the SGLT2-i empagliflozin suppresses mitochondrial-ROS generation and mitigates fibrosis. MethodsA high-fat diet and low-dose streptozotocin treatment were used to induce type-2 DM (T2DM) in Sprague-Dawley rats. The rats were randomly divided into three groups: control, DM, and DM treated with empagliflozin (30 mg/kg/day) for 8 weeks. The mitochondrial respiratory capacity and ROS generation in the atrial myocardium were measured using a high-resolution respirometer. Oxidative stress markers and protein expression related to mitochondrial biogenesis and dynamics as well as the mitochondrial morphology were examined in the atrial tissue. Additionally, mitochondrial function was examined in H9c2 cardiomyoblasts. Atrial tachyarrhythmia (ATA) inducibility, interatrial conduction time (IACT), and fibrosis were also measured. ResultsInducibility of ATA, fibrosis, and IACT were increased in rats with DM when compared to controls, all of which were restored by empagliflozin treatment. In addition, the rats with DM had increased mitochondrial-ROS with an impaired complex I-linked oxidative phosphorylation capacity. Importantly, empagliflozin seemed to ameliorate these impairments in mitochondrial function. Furthermore, empagliflozin reversed the decrease in phosphorylated AMPK expression and altered protein levels related to mitochondrial biogenesis and dynamics, and increased mitochondrial content. Empagliflozin also improved mitochondrial function in H9c2 cells cultured with high glucose medium. DiscussionThese data suggest that empagliflozin has a cardioprotective effect, at least in part, by reducing mitochondrial ROS generation through AMPK signaling pathways in the atrium of diabetic rats. This suggests that empagliflozin might suppress the development of AF in T2DM.
Type: article
Appears in Collections:北海道大学病院 (Hokkaido University Hospital) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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