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Dapagliflozin Protects Methamphetamine-Induced Cardiomyopathy by Alleviating Mitochondrial Damage and Reducing
Shanqing He1,2,3, Yajun Yao1,2,3, Nan Yang4
1Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
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.
Insights
Dapagliflozin (DAPA) prevents methamphetamine (METH)-induced cardiomyopathy in mice. DAPA protects the heart by reducing mitochondrial damage and apoptosis, offering a potential therapeutic strategy for METH toxicity.
Area of Science:
- Cardiology
- Pharmacology
- Toxicology
Background:
- Methamphetamine (METH) causes cardiovascular toxicity, partly due to mitochondrial dysfunction.
- Dapagliflozin (DAPA) has shown cardiovascular benefits, but its effect on METH-induced cardiomyopathy is unknown.
Purpose of the Study:
- To investigate DAPA's potential to prevent METH-induced cardiomyopathy.
- To evaluate DAPA's effects on cardiac function, oxidative stress, mitochondrial damage, and apoptosis in a METH-exposed mouse model.
Main Methods:
- C57BL/6 mice were administered METH for 14 weeks, with one group receiving concurrent DAPA treatment.
- Cardiac function was assessed via echocardiography.
- Oxidative stress, mitochondrial damage, and apoptosis were evaluated using ROS, JC-1, and TUNEL assays, respectively.
- Mitochondrial and apoptosis-related protein expression was analyzed by western blotting.
Main Results:
- METH exposure led to reduced cardiac function (LVEF decline), fibrotic remodeling, mitochondrial dysfunction, and increased apoptosis.
- DAPA treatment significantly improved cardiac function (LVEF preserved), reduced fibrotic remodeling, decreased oxidative stress (ROS), and attenuated mitochondrial damage and apoptosis.
- DAPA treatment resulted in significantly lower apoptotic cell percentages (2.4% vs. 7.4%) and preserved cardiac function (LVEF 70.9% vs. 56.5%) compared to METH-only group.
Conclusions:
- Dapagliflozin (DAPA) demonstrates a protective effect against methamphetamine (METH)-induced cardiomyopathy in mice.
- DAPA mitigates METH cardiotoxicity by reducing mitochondrial damage and apoptosis.
- These findings suggest DAPA as a potential therapeutic agent for METH-associated cardiovascular complications.
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