黄芪甲苷IV通过DUSP1-Prohibitin 2介导的线粒体质量控制与内质网自噬减轻脓毒症心肌损伤

INTRODUCTION: Septic cardiomyopathy (SCM) is a complication of myocardial injury in patients with severe sepsis.OBJECTIVES: This study highlights the potential of Astragaloside IV(AS) in the treatment of septic cardiomyopathy and provides a reference for developing cardioprotective drugs targeting DUSP1-PHB2-related mitochondria-ER interaction.METHODS: Dual specificity phosphatase-1 (DUSP1)/Prohibitin 2 cardiomyocyte-specific knockout mice (DUSP1/PHB2CKO) /DUSP1 transgenic mice (DUSP1/PHB2TG) were used to generate LPS-induced sepsis models. The pathological mechanism by which AS-IV improves heart injury was detected using cardiac ultrasound, fluorescence staining, transmission electron microscopy, and western blotting. After siRNA treatment of cardiomyocytes with DUSP-1/PHB2, changes in mitochondrial function and morphology were determined using qPCR, western blotting, ELISA, and laser confocal microscopy, and the targeted therapeutic effects of AS-IV were further examined.RESULTS: SCM treatment leads to severe mitochondrial dysfunction. However, Astragaloside IV (AS) treatment normalizes mitochondrial homeostasis and ER function. Notably, the protective effect was blocked in DUSP1/Prohibitin 2 cardiomyocyte-specific knockout mice (DUSP1/PHB2CKO) but remained unaffected in DUSP1 transgenic mice (DUSP1/PHB2TG).CONCLUSION: This study highlights the potential of AS in the treatment of septic cardiomyopathy and provides a reference for developing cardioprotective drugs targeting DUSP1-PHB2 related mitochondria-ER interaction.