Acta Diabetol. 2025 Aug 23. doi: 10.1007/s00592-025-02579-z. Online ahead of print.
ABSTRACT
AIMS: This study tested the hypothesis that the anti-diabetes drug dapagliflozin (DAPA) alleviates heart dysfunction induced by type 3 cardiorenal syndrome (CRS-3) by normalizing mitochondrial quality control (MQC). MQC is a stress-activated mechanism, regulated by Dual specificity phosphatase 1 (DUSP1), that maintains mitochondrial homeostasis to support heart function. Due to its known renal and cardioprotective effects, DAPA was investigated as a potential treatment for CRS-3.
METHODS: CRS-3 was induced in mice through renal ischemia/reperfusion. The effects of DAPA pre-treatment were assessed by measuring heart function, serum levels of myocardial injury biomarkers, oxidative stress, inflammation, and cardiomyocyte apoptosis. Assays in cardiomqyocytes from CRS-3 mice were used to analyze MQC, including mitochondrial dynamics, mitophagy, and biogenesis. The role of DUSP1 was investigated using DUSP1-knockout mice, and a docking analysis was performed to assess the DAPA-DUSP1 interaction.
RESULTS: DAPA pre-treatment dose-dependently improved heart function and reduced serum markers of myocardial injury, oxidative stress, inflammation, and cardiomyocyte apoptosis in CRS-3 mice. DAPA treatment stabilized MQC in cardiomyocytes, shown by improved mitochondrial dynamics and restored mitophagy and biogenesis. Docking analysis suggested that DAPA directly interacts with DUSP1 and suppresses its nuclear translocation. Notably, in DUSP1-knockout mice, the stabilizing effect of DAPA on MQC was abolished. Furthermore, upon DUSP1 deletion, DAPA failed to prevent CRS-3-related oxidative stress, inflammation, apoptosis, and heart dysfunction.
CONCLUSIONS: Defective MQC critically contributes to CRS-3-related myocardial dysfunction. The study proposes that DAPA therapy may normalize DUSP1-dependent MQC and consequently alleviate the cardiac depression associated with CRS-3.
PMID:40848132 | DOI:10.1007/s00592-025-02579-z
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