Astragaloside IV attenuates uremia-induced myocardial injury by inhibiting autophagy via ATF4.

BACKGROUND: Cardiovascular diseases (CVDs) are one of the primary causes of mortality in patients with uremia. The therapeutic value of intravenous Astragaloside (AS-IV) in the treatment of CVDs has been widely recognized. However, whether AS-IV treats CVDs complicated by uremia remains unknown. This study aimed to determine the effects and potential mechanisms of AS-IV in the treatment of CVDs associated with uremia. METHODS: The 5/6 nephrectomized mouse model and uremic serum (US)-induced myocardial injury model of H9C2 cells were established in this study. Various techniques, including echocardiography, ELISA, TUNEL assay, flow cytometry, Western blotting, immunofluorescence, transmission electron microscopy, and qRT-PCR, were employed to investigate the effects of AS-IV on uremia-associated myocardial injury and determine its impact on autophagy and related signaling pathways. An ATF4 inhibitor and plasmid transfection techniques were used to modulate ATF4 expression and investigate the role of ATF4 in the protective effects of AS-IV on myocardial injury. RESULTS: AS-IV significantly improved cardiorenal function and attenuated uremia-associated cardiomyocyte apoptosis in 5/6 nephrectomized mice. Autophagy was significantly activated, and ATF4 expression was increased in 5/6 nephrectomized mice and uremic toxin-treated cardiomyocytes. AS-IV also significantly inhibited ATF4 expression and cardiomyocyte autophagy. Inhibition of ATF4 expression reduced cardiomyocyte apoptosis, while ATF4 overexpression significantly attenuated the cardioprotective effects of AS-IV. AS-IV significantly activated the PI3K pathway, while modulation of ATF4 expression affected AS-IV-mediated activation of the PI3K pathway. CONCLUSIONS: AS-IV ameliorated uremia-associated myocardial injury by suppressing ATF4 expression and regulating cardiomyocyte autophagy. The PI3K pathway may modulate autophagy after treatment with AS-IV.