Published online Dec 15, 2023. doi: 10.4239/wjd.v14.i12.1862
Peer-review started: September 21, 2023
First decision: October 10, 2023
Revised: October 20, 2023
Accepted: November 17, 2023
Article in press: November 17, 2023
Published online: December 15, 2023
Processing time: 83 Days and 20.1 Hours
Diabetic cardiomyopathy (DCM) increases the risk of hospitalization for heart failure (HF) and mortality in patients with diabetes mellitus. However, no specific therapy to delay the progression of DCM has been identified. Mitochondrial dysfunction, oxidative stress, inflammation, and calcium handling imbalance play a crucial role in the pathological processes of DCM, ultimately leading to cardio
To investigate the effects of empagliflozin on high glucose (HG)-induced oxidative stress and cardiomyocyte apoptosis and the underlying molecular mechanism.
Twelve-week-old db/db mice and primary cardiomyocytes from neonatal rats stimulated with HG (30 mmol/L) were separately employed as in vivo and in vitro models. Echocardiography was used to evaluate cardiac function. Flow cytometry and TdT-mediated dUTP-biotin nick end labeling staining were used to assess apoptosis in myocardial cells. Mitochondrial function was assessed by cellular ATP levels and changes in mitochondrial membrane potential. Furthermore, intracellular reactive oxygen species production and superoxide dismutase activity were analyzed. Real-time quantitative PCR was used to analyze Bax and Bcl-2 mRNA expression. Western blot analysis was used to measure the phos
In the in vivo experiment, db/db mice developed DCM. However, the treatment of db/db mice with empagliflozin (10 mg/kg/d) for 8 wk substantially enhanced cardiac function and significantly reduced myocardial apoptosis, accompanied by an increase in the phosphorylation of AMPK and PGC-1α protein levels, as well as a decrease in the phosphorylation of MYPT1 in the heart. In the in vitro experiment, the findings indicate that treatment of cardiomyocytes with empagliflozin (10 μM) or fasudil (FA) (a ROCK inhibitor, 100 μM) or overexpression of PGC-1α significantly attenuated HG-induced mitochondrial injury, oxidative stress, and cardiomyocyte apoptosis. However, the above effects were partly reversed by the addition of compound C (CC). In cells exposed to HG, empagliflozin treatment increased the protein levels of p-AMPK and PGC-1α protein while decreasing phos
Empagliflozin partially achieves anti-oxidative stress and anti-apoptotic effects on cardiomyocytes under HG conditions by activating AMPK/PGC-1α and suppressing of the RhoA/ROCK pathway independent of SGLT2.
Core Tip: We established a diabetic cardiomyopathy model in db/db mice and treated the mice with empagliflozin for 8 wk, and found that empagliflozin observably improved cardiac function in diabetic mice, which was maybe related to activation of AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and inhibition of the RhoA/ROCK pathway. In order to exclude the effects of metabolic improvement on the heart in vivo, in vitro experiment in high glucose conditions was performed. The results confirmed that the anti-oxidative stress and anti-apoptotic effects of empagliflozin on cardiomyocytes were achieved by activating AMPK/PGC-1α and inhibiting ROCK. Furthermore, the effects were independent of sodium-glucose cotransporter (SGLT)2 inhibition as no SGLT2 expression was detected on cardiomyocytes.