Related Experiment Video
Updated: Oct 29, 2025
Optimization of Transesophageal Atrial Pacing to Assess Atrial Fibrillation Susceptibility in Mice
Published on: June 29, 2022
Dapagliflozin attenuates arrhythmic vulnerabilities by regulating connexin43 expression via the AMPK pathway in
Cheng-Che Lee1, Wei-Ting Chen2, Syue-Yi Chen2
1Kang-Ming Senior High School, Tainan, Taiwan.
Abstract:
We have demonstrated that dapagliflozin, a sodium-glucose cotransporter (SGLT) 2 inhibitor, attenuates reactive oxygen species (ROS) production. Connexin43 playing a role in ventricular arrhythmia is sensitive to redox status. No data are available on the effects of dapagliflozin on arrhythmogenesis. This study was to determine whether dapagliflozin attenuated arrhythmias through modulating AMP-activated protein kinase (AMPK)/free radicals-induced connexin43 after myocardial infarction. After coronary ligation, normoglycemic male Wistar rats were randomized to either vehicle or dapagliflozin (0.1 mg/kg per day) for 4 weeks. Myocardial ROS levels were significantly increased (p < 0.05) and connexin43 levels were substantially decreased after myocardial infarction (p < 0.05). Dapagliflozin administration was associated with increased SGLT1, attenuated ROS and increased connexin43 levels in myocardium (all p < 0.05). During programmed electrical stimulation, arrhythmic severity was significantly improved in the dapagliflozin-treated infarcted rats than those in the vehicle-treated infarcted rats (p < 0.05). Dapagliflozin significantly increased AMPK phosphorylation compared to vehicle after infarction (p < 0.05). Inhibition of AMPK signaling by SBI-0206965 prevented increased SGLT1 and blocked the effects of dapagliflozin on attenuated ROS levels and increased connexin43 phosphorylation (all p < 0.05). SGLT1 inhibited by KGA-2727 showed attenuated ROS levels and increased connexin43 phosphorylation (both p < 0.05) although AMPK phosphorylation was not changed, implying SGLT1 activation was mediated by AMPK in dapagliflozin-treated hearts. Dapagliflozin-treated hearts had significantly increased connexin43 phosphorylation (p < 0.05), which was significantly decreased after adding 3-morpholinosydnonimine (p < 0.05). These data indicate that clinically-relevant dapagliflozin concentrations decreased free radicals content and increased connexin43 levels through AMPK-dependent and SGLT1-independent mechanisms, which attenuated ventricular arrhythmias in the normoglycemic infarcted rats.
Insights
Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, reduces arrhythmias after myocardial infarction by decreasing reactive oxygen species and increasing connexin43 levels. This protective effect is mediated through AMP-activated protein kinase signaling pathways.
Area of Science:
- Cardiology
- Pharmacology
- Biochemistry
Background:
- Ventricular arrhythmias post-myocardial infarction are linked to altered redox status and connexin43 levels.
- Sodium-glucose cotransporter 2 (SGLT2) inhibitors like dapagliflozin are known to reduce reactive oxygen species (ROS) production.
- The specific effects of dapagliflozin on arrhythmogenesis, particularly its impact on connexin43 and associated signaling pathways, remain largely uninvestigated.
Purpose of the Study:
- To investigate whether dapagliflozin attenuates ventricular arrhythmias following myocardial infarction.
- To elucidate the underlying mechanisms, focusing on the modulation of AMP-activated protein kinase (AMPK), ROS, and connexin43.
- To determine the role of SGLT1 and AMPK signaling in dapagliflozin's anti-arrhythmic effects.
Main Methods:
- Normoglycemic male Wistar rats underwent coronary ligation to induce myocardial infarction.
- Rats were randomized to receive either vehicle or dapagliflozin (0.1 mg/kg/day) for 4 weeks.
- Assessment of myocardial ROS, connexin43 levels, AMPK phosphorylation, and arrhythmogenic severity via programmed electrical stimulation. Specific inhibitors were used to probe signaling pathways.
Main Results:
- Dapagliflozin treatment significantly attenuated ROS production and increased connexin43 levels in infarcted rat myocardium (p < 0.05).
- Arrhythmic severity was significantly reduced in dapagliflozin-treated rats compared to controls (p < 0.05).
- Dapagliflozin administration led to increased AMPK phosphorylation, and this effect was blocked by AMPK inhibition. SGLT1 inhibition also affected ROS and connexin43 levels, suggesting complex interactions.
Conclusions:
- Dapagliflozin exerts anti-arrhythmic effects in normoglycemic infarcted rats by reducing ROS and increasing connexin43 levels.
- These cardioprotective effects are mediated, at least in part, through an AMPK-dependent mechanism.
- The findings suggest a novel therapeutic potential for dapagliflozin in managing post-myocardial infarction arrhythmias.
More Related Videos
05:41Left Anterior Descending Coronary Artery Ligation for Ischemia-Reperfusion Research: Model Improvement via Technical Modifications and Quality Control
Published on: December 16, 2022
05:12Transesophageal Atrial Burst Pacing for Atrial Fibrillation Induction in Rats
Published on: February 14, 2022
Related Concept Videos
01:12Antiarrhythmic Drugs: Class III Agents as Potassium Channel Blockers
01:26Heart Failure Drugs: Inhibitors of Renin-Angiotensin System
01:28Mechanism of Cardiac Arrhythmias
01:22Antiarrhythmic Drugs: Class I Agents as Sodium Channel Blockers
Class 1A Antiarrhythmic Drugs: These drugs work by moderately blocking sodium channels,...
01:26Heart Failure Drugs: Inotropic Agents