Dapagliflozin Protects Methamphetamine-Induced Cardiomyopathy by Alleviating Mitochondrial Damage and Reducing Cardiac Function Decline in a Mouse Model

Abstract

Background: Methamphetamine (METH)-induced cardiovascular toxicity has been attributed to its destructive effect on mitochondrial function at least to some extent. Previous studies highlighted the benefits of dapagliflozin (DAPA) on the cardiovascular system, but the response of METH-induced cardiomyopathy to DAPA is never addressed before. The present study aimed to investigate the potential ability of DAPA in preventing METH-induced cardiomyopathy.Materials and Methods: C57BL/6 mice were randomly divided into control group (n = 24), METH group (n = 24), and METH + DAPA group (n = 24). The METH-induced cardiomyopathy group received intraperitoneal METH injections at gradually increasing doses thrice weekly for 14 weeks. Mice in the METH + DAPA group were simultaneously treated with DAPA 1 mg/kg/day by intragastric administration. Echocardiography was performed to assess cardiac function. Reactive oxygen species (ROS), JC-1, and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays were performed to evaluate oxidative stress, mitochondrial damage, and apoptosis, respectively. Mitochondrial and apoptosis-related protein expression was measured by western blotting.Results: Mice exposed to METH exhibited reduced cardiac function (left ventricular ejection fraction [LVEF]: 56.51 ± 6.49 vs. 73.62 ± 1.42, p < 0.01), fibrotic remodeling, and mitochondrial dysfunction, leading to apoptosis (apoptotic cells%: 7.4 ± 1.3 vs. 1.3 ± 0.5, p < 0.01). DAPA significantly reduced mitochondrial dynamics and function, ROS, apoptosis (apoptotic cells%: 2.4 ± 0.8 vs. 7.4 ± 1.3, p < 0.01), cardiac function decline (LVEF: 70.99 ± 4.936 vs. 56.51 ± 6.49, p < 0.01), and fibrotic remodeling. These results indicated that DAPA could be considered as an effective therapeutic agent in the protection against METH-associated cardiomyopathy.Conclusion: DAPA protects against METH-induced cardiomyopathy in mice by decreasing mitochondrial damage and apoptosis.

Dapagliflozin alleviates myocardial ischemia/reperfusion injury by reducing ferroptosis via MAPK signaling inhibition

“…DAPA showed a 1200-fold selectivity for SGLT2 over SGLT1 ( Zugner et al, 2022 ), and the effects of DAPA on mitochondrial complex I activity and amino acid metabolites have been reported ( Uthman et al, 2019 ; Mulder et al, 2020 ). Animal studies have suggested that DAPA may protect the myocardium from myocardial infarction ( Yu et al, 2021 ), obesity-related cardiomyopathy ( Lin K. et al, 2022 ), and methamphetamine-induced cardiomyopathy ( He S. et al, 2022 ). Cardiomyocytes and cardiac tissues lack SGLT2 expression, and the cardioprotective effects of SGLT2 inhibitors should be mediated by other targets and signaling pathways.…”

Dapagliflozin Suppresses Isoprenaline-Induced Cardiac Hypertrophy via Inhibition of Mitochondrial Fission

“… 18 Some studies reported that DAPA attenuated cardiomyopathy by means of decreasing mitochondrial damage and apoptosis. 19 A previous study 9 showed that DAPA attenuated cardiac hypertrophy. Our study is consistent with it.…”