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

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.

The changes of cardiac energy metabolism with sodium-glucose transporter 2 inhibitor therapy

“…The results demonstrated that the pro-fusion proteins MFN1/2 and OPA1 were upregulated, and the pro-fission proteins DRP1 and FIS1 were downregulated after SGLT2i treatment ( 35 , 42 , 47 ). According to Koizumi et al, Empagliflozin brought the altered atrial protein expression associated with fission and fusion of mitochondria back to levels comparable to those observed in the control group ( 139 ). Additionally, 6 studies showed that SGLT2i increased the mitochondria number ( 34 ), length ( 35 ), pleomorphism ( 30 , 35 ), mean area ( 34 , 39 ) and MMP ( 42 , 47 ) while alleviating mitochondria irregular swelling, fractured cristae and fuzziness ( 35 ), implying an improvement in mitochondria structure.…”

Developing Pharmacological Therapies for Atrial Fibrillation Targeting Mitochondrial Dysfunction and Oxidative Stress: A Scoping Review

“…A recent analysis of the DECLARE-TIMI 58 study showed a 19% reduction in the incidence of AF in patients with diabetes, regardless of pre-existing AF or HF. Effective AF prevention can transform this approach into HF treatment [ 39 , 40 , 41 ].…”

“…NOX has multiple isoforms that can influence various processes and contribute to chronic diseases, such as hypertension, hyperlipidemia, and HF [40]. Cardiovascular-related isoforms, NOX2 and NOX4, inhibit atrial remodeling and reduce inflammation associated with AF [40,41]. NOX activity is exacerbated in fibrillating atria, especially in the presence of systemic hormones such as Ang II and aldosterone [39].…”

Sodium–Glucose Cotransporter-2 Inhibitor, Empagliflozin, Suppresses the Inflammatory Immune Response to Influenza Infection

“…It has been shown that empagliflozin reduces reactive oxygen species and improves mitochondrial function ( 25 ). In our study, we found that empagliflozin reduces NOS2 expression, suggesting that empagliflozin reduces the induction of reactive nitrogen species, thereby reducing the mitochondrial oxidative stress ( Fig.…”