Acute dapagliflozin administration exerts cardioprotective effects in rats with cardiac ischemia/reperfusion injury

Sarayut Lahnwong, Siripong Palee, Nattayaporn Apaijai, Sirawit Sriwichaiin, Sasiwan Kerdphoo, Thidarat Jaiwongkam, Siriporn C Chattipakorn, Nipon Chattipakorn, Sarayut Lahnwong, Siripong Palee, Nattayaporn Apaijai, Sirawit Sriwichaiin, Sasiwan Kerdphoo, Thidarat Jaiwongkam, Siriporn C Chattipakorn, Nipon Chattipakorn

Abstract

Background: A sodium-glucose co-transporter 2 (SGLT-2) inhibitor had favorable impact on the attenuation of hyperglycemia together with the severity of heart failure. However, the effects of acute dapagliflozin administration at the time of cardiac ischemia/reperfusion (I/R) injury are not established.

Methods: The effects of dapagliflozin on cardiac function were investigated by treating cardiac I/R injury at different time points. Cardiac I/R was instigated in forty-eight Wistar rats. These rats were then split into 4 interventional groups: control, dapagliflozin (SGLT2 inhibitor, 1 mg/kg) given pre-ischemia, at the time of ischemia and at the beginning of reperfusion. Left ventricular (LV) function and arrhythmia score were evaluated. The hearts were used to evaluate size of myocardial infarction, cardiomyocyte apoptosis, cardiac mitochondrial dynamics and function.

Results: Dapagliflozin given pre-ischemia conferred the maximum level of cardioprotection quantified through the decrease in arrhythmia, attenuated infarct size, decreased cardiac apoptosis and improved cardiac mitochondrial function, biogenesis and dynamics, leading to LV function improvement during cardiac I/R injury. Dapagliflozin given during ischemia also showed cardioprotection, but at a lower level of efficacy.

Conclusions: Acute dapagliflozin administration during cardiac I/R injury exerted cardioprotective effects by attenuating cardiac infarct size, increasing LV function and reducing arrhythmias. These benefits indicate its potential clinical usefulness.

Keywords: Dapagliflozin; Heart; Ischemia–reperfusion injury; Mitochondria; Sodium-glucose co-transporter 2 (SGLT-2) inhibitors.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
The protocol used to show the dapagliflozin effects on myocardial and mitochondrial function given at pre-ischemic, during ischemic and onset of reperfusion time points during acute I/R injury in rats, n = 12 per group. TTC triphenyltetrazolium chloride
Fig. 2
Fig. 2
The effects of dapagliflozin on myocardial infarction in rats with cardiac I/R injury. a Area at risk, n = 6 per group; and b Myocardial infarct size, n = 6 per group. *p < 0.05 vs control and †p < 0.05 vs pretreatment group. AAR area at risk
Fig. 3
Fig. 3
The effects of dapagliflozin on cardiac arrhythmia and gap junction-related proteins in rats with I/R injury. a Time to 1st VT/VF, n = 6 per group; b Arrhythmia score, n = 6 per group; c p-Cx43 Ser368/Cx43 protein expression in the ischemic area normalized with that in the remote area, n = 6 per group; and d Representative Western blot bands of p-Cx43 Ser368 and Cx43 proteins expression in the ischemic area and the remote area. *p < 0.05 vs control and †p < 0.05 vs pretreatment group. Cx43 connexin, I ischemic area, p-Cx43 Ser638 phosphorylation of Cx43 at serine638, R remote area, VF ventricular fibrillation, VT ventricular tachycardia
Fig. 4
Fig. 4
The effects of dapagliflozin on left ventricular function in rats with I/R injury. a Heart rate; b Stroke volume; c Left ventricular end systolic pressure; d Left ventricular end diastolic pressure; edP/dtmax; fdP/dtmin; and g Left ventricular ejection fraction, n = 6 per group. *p < 0.05 vs baseline of its group; †p < 0.05 vs control group at that period. dP/dt ventricular contractility assessment, EDP end diastolic pressure, ESP end systolic pressure, HR heart rate, LVEF left ventricular ejection fraction, SV stroke volume
Fig. 5
Fig. 5
The effects of dapagliflozin on cardiac cell apoptosis in rats with cardiac I/R injury. a Bax; b Bcl-2; c Caspase-3; and d Cleaved caspase-3 expression in the ischemic area normalized with that in the remote area, n = 6 per group. *p < 0.05 vs control. I ischemic area, R remote area
Fig. 6
Fig. 6
The effect of dapagliflozin on TUNEL-positive cells in the heart. a Representative images of TUNEL-positive cells; b Apoptotic index, n = 4 per group. *p < 0.05 vs control; †p < 0.05 vs pretreatment group; ‡p < 0.05 vs during ischemia
Fig. 7
Fig. 7
The effects of dapagliflozin on cardiac mitochondrial function in rats with cardiac I/R injury. a Mitochondrial ROS production; b Mitochondrial membrane potential changes; and c Mitochondrial swelling, n = 6 per group. *p < 0.05 vs control. MMP mitochondrial membrane potential, ROS reactive oxygen species
Fig. 8
Fig. 8
The effects of dapagliflozin on proteins associated with myocardial metabolism and oxidative phosphorylation in rats with I/R injury. a Myocardial PGC1-α; b Myocardial CPT-1; and c Cardiac mitochondrial complex I–V expression in the ischemic area normalized with that in the remote area, n = 6 per group. *p < 0.05 vs control. CPT1 carnitine palmitoyltransferase I, GAPDH glyceraldehyde 3-phosphate dehydrogenase, I ischemic area, PGC1-α peroxisome proliferator-activated receptor gamma coactivator 1-alpha, R remote area, VDAC voltage-dependent anion channel
Fig. 9
Fig. 9
The effects of dapagliflozin on the expression of cardiac mitochondrial fission and fusion protein in rats with I/R injury. a Cardiac mitochondrial DRP1; b MFN2; c OPA1 expression in the ischemic area normalized with that in the remote area, n = 6 per group; and d Representative western blot bands of a–c. *p < 0.05 vs control. DRP1 dynamin-related protein 1, I ischemic area, MFN2 mitofusin 2, OPA1 optic atrophy 1, R remote area, VDAC voltage-dependent anion channel

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