Astragaloside IV attenuates uremia-induced myocardial injury by inhibiting autophagy via ATF4
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Background Cardiovascular pathology is one of the primary causes of mortality in patients with uremia. The therapeutic value of intravenous Astragaloside (AS-IV)in the treatment of cardiovascular diseases (CVDs) has been widely recognized. However, research on its treatment ofCVDs complicated by uremia remains extremely limited. The aim of this study was therefore to determine the effects and potential mechanisms of AS-IV in the treatment of CVD associated with uremia. Methods The 5/6 nephrectomized mouse and uremic serum-induced myocardial injury model of H9C2 cells were constructed. A variety of techniques, including echocardiography, ELISA, TUNEL assay, flow cytometry, Western blotting, immunofluorescence, transmission electron microscopy,andqRT-PCRwere used to investigate the effects of AS-IV on uremia-associated myocardial injury and its impact on autophagy and related signaling pathway proteins. An ATF4 inhibitor and plasmid transfection techniques were used to modulate ATF4 expression and investigate the role of ATF4 in AS-IV-mediated protection against myocardial injury. Results AS-IVsignificantly improved cardiorenal function and attenuated uremia-associated cardiomyocyte apoptosis in the 5/6 nephrectomized mice. Autophagy levels were activated significantly and ATF4 expression was increased significantly in these mice and uremic toxin-treated cardiomyocytes. AS-IV also significantly inhibited ATF4 expression and cardiomyocyte autophagy. Inhibition of ATF4 expression reduced cardiomyocyte apoptosis, while overexpression of ATF4 significantly attenuated the cardioprotective effects of AS-IV. AS-IV significantly activated the PI3K pathway, while modulation of ATF4 expression affected activation of the PI3K pathway by AS-IV. Conclusions AS-IVameliorates uremia-associated myocardial injury by suppressing ATF4 expression and regulating cardiomyocyte autophagy activity. The PI3K pathway may be involved in this modulation of autophagy.
