Astragaloside IV Attenuates Heart Failure by Modulating SCAD/DJ-1/SIRT1/FOXO3a Signaling Axis

As the key functioning element of the traditional Chinese medicinal herb Astragalus, Astragaloside IV (AS-IV) has potentially protective effects on heart failure (HF). Short-chain Acyl-CoA dehydrogenase (SCAD) is a critical enzyme in fatty acid β-oxidation, which negatively regulates cardiomyocyte apoptosis and HF. However, the molecular mechanism by which AS-IV influences myocardial energy metabolism in HF remains uncertain. In this study, we aim to both explore the underlying mechanisms of AS-IV in protecting against HF and provide potential directions for the clinical use of AS-IV. In vivo, an HF model was induced in mice using transverse aortic constriction (TAC) surgery in order to examine echocardiography, cell apoptosis, energy metabolism, oxidative stress, and signaling molecules. In vitro, a cell apoptosis model was stimulated by tert-butyl hydroperoxide (tBHP) in H9C2 cardiomyocytes. SCAD or DJ-1 was silenced using small interfering RNA. In vivo results demonstrated that AS-IV significantly ameliorated cardiac function and myocardial fibrosis, enhanced energy metabolism, and reduced both cell apoptosis and oxidative stress. Mechanistically, AS-IV activated SCAD/DJ-1/SIRT1/FOXO3a signaling axis in HF mice. This mechanism was further validated in vitro, as the knockdown of SCAD or DJ-1 attenuated the anti-apoptotic effect of AS-IV and the regulation of signaling axis in an H9C2 cardiomyocyte apoptosis model. These findings show that AS-IV improves myocardial energy metabolism to decrease oxidative stress and cardiomyocyte apoptosis via the SCAD/DJ-1/SIRT1/FOXO3a signaling axis, and therefore suggest its potential as a therapeutic agent for HF.