Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology · 2025
Dapagliflozin alleviates isoprenaline-induced cardiac hypertrophy by promoting mitophagy via AMPKα2 signaling pathway.
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Feng Yue, Zhu Zixiong, Jing Xin, Zhang Yibo, He Yubin, Li Xuewen
Аннотация
INTRODUCTION AND OBJECTIVES: The global prevalence of heart failure (HF) has been increasing in recent years, posing a significant threat to human health. Several studies have shown that impaired mitophagy accelerates HF progression. Dapagliflozin (DAPA) has demonstrated cardioprotective effects in HF patients. This study aims to investigate the therapeutic effects of DAPA on cardiomyocyte hypertrophy and its underlying mechanism.
METHODS: The working concentration of isoprenaline (ISO) was determined through combined quantitative real-time polymerase chain reaction (qPCR) and CCK-8 assays. H9c2 cells were stimulated with ISO to induce a hypertrophy model. Cellular hypertrophy was quantified by qPCR and TRITC-phalloidin staining. Mitochondrial ultrastructure and functional integrity was assessed by transmission electron microscopy and JC-1 staining. Mitophagy levels were measured using Western blotting and co-localization assays. AMPKα2 expression levels were determined via Western blotting. Following AMPKα2 siRNA transfection, cellular hypertrophy and mitophagy levels were reassessed.
RESULTS: ISO markedly induced cardiomyocyte hypertrophy, mitochondrial damage and mitophagy inhibition, whereas DAPA effectively attenuated these pathologica changes, with AMPK agonists demonstrating comparable cardioprotective effects. In ISO-treated H9c2 cells, AMPKα2 expression was reduced, while DAPA significantly upregulated its expression. Notably, AMPKα2 inhibition significantly weakened DAPA's protective effect on ISO-induced hypertrophy and mitochondrial injury.
CONCLUSION: DAPA exerts cardioprotective effects by mitigating ISO-induced cardiac hypertrophy and preserving mitochondrial integrity, mediated through AMPKα2-dependent activation of mitophagy.
METHODS: The working concentration of isoprenaline (ISO) was determined through combined quantitative real-time polymerase chain reaction (qPCR) and CCK-8 assays. H9c2 cells were stimulated with ISO to induce a hypertrophy model. Cellular hypertrophy was quantified by qPCR and TRITC-phalloidin staining. Mitochondrial ultrastructure and functional integrity was assessed by transmission electron microscopy and JC-1 staining. Mitophagy levels were measured using Western blotting and co-localization assays. AMPKα2 expression levels were determined via Western blotting. Following AMPKα2 siRNA transfection, cellular hypertrophy and mitophagy levels were reassessed.
RESULTS: ISO markedly induced cardiomyocyte hypertrophy, mitochondrial damage and mitophagy inhibition, whereas DAPA effectively attenuated these pathologica changes, with AMPK agonists demonstrating comparable cardioprotective effects. In ISO-treated H9c2 cells, AMPKα2 expression was reduced, while DAPA significantly upregulated its expression. Notably, AMPKα2 inhibition significantly weakened DAPA's protective effect on ISO-induced hypertrophy and mitochondrial injury.
CONCLUSION: DAPA exerts cardioprotective effects by mitigating ISO-induced cardiac hypertrophy and preserving mitochondrial integrity, mediated through AMPKα2-dependent activation of mitophagy.