Empagliflozin Attenuates Left Ventricular Remodeling in Diabetic Rats: Involvement of SIRT1/PINK1 Signaling

Objective: To explore the role of sirtuin 1 (SIRT1)/PTEN-induced kinase 1 (PINK1) signaling in diabetic ventricular remodeling and investigate the effects of empagliflozin on this process. Method: Diabetes mellitus was induced in male Sprague-Dawley rats using a high-fat diet combined with low-dose streptozotocin. Successfully induced diabetic rats were enrolled in batches and randomly assigned to the diabetes mellitus, low-dose empagliflozin (10 mg/kg daily), or high-dose empagliflozin (30 mg/kg daily) group. The first batch included 6 rats per group, and additional rats were enrolled in the second batch to reach a final sample size of 8 rats per group. Age-matched non-diabetic rats served as controls ( n = 8). After 8 weeks of treatment, cardiac structure and function were evaluated by echocardiography and invasive hemodynamic measurements, and myocardial hypertrophy and fibrosis were assessed histologically. Mitochondrial respiratory function and membrane potential were evaluated by respiratory control ratio and JC-1 fluorescence, respectively. SIRT1, nuclear respiratory factor 1 (NRF-1), and PINK1 protein expression levels were assessed by Western blotting. In H9c2 cells exposed to high glucose, the involvement of SIRT1 signaling was further investigated using the SIRT1 inhibitor EX527 and SIRT1-specific small interfering RNA. Result: Compared with control rats, diabetic rats exhibited greater left atrial diameter, interventricular septal thickness, left ventricular posterior wall thickness, cardiomyocyte cross-sectional area, and myocardial fibrosis, together with impaired diastolic and hemodynamic function (all P < 0.05). Empagliflozin treatment attenuated these structural and functional abnormalities, although the significant effects varied according to dose. The mitochondrial respiratory control ratio and JC-1 red/green fluorescence ratio were significantly lower in diabetic rats than in controls (both P < 0.001) and were significantly higher following empagliflozin treatment (all P < 0.05). SIRT1, NRF-1, and PINK1 protein expression levels were significantly lower in diabetic myocardium and high-glucose-exposed H9c2 cells than in corresponding controls (all P < 0.05). In H9c2 cells, SIRT1 inhibition with EX527 was associated with lower SIRT1, NRF-1, and PINK1 protein expression following EMPA treatment (all P < 0.05). Conclusion: Empagliflozin attenuated left ventricular remodeling and improved mitochondrial function in diabetic rats, with SIRT1/PINK1 signaling potentially contributing to these beneficial effects.