Astragalus membranaceus injection may protect heart cells in chronic heart failure by activating mitochondrial cleanup through AKT/mTOR pathway inhibition
Astragalus membranaceus injection protected hypertrophic cardiomyocytes and pressure-overload heart-failure mice by restoring through AKT/mTOR inhibition.
Evidence
This preclinical cell and mouse study used PE-stimulated neonatal mouse cardiomyocytes, TAC-induced chronic heart failure mice, phosphoproteomics, network pharmacology, and AKT/mTOR activator-inhibitor experiments.
Caveat
The findings come from mouse cells and mice, so they do not establish clinical benefit or dosing in human chronic heart failure.
Simplified
To investigate the effects and mechanisms of Astragalus Membranaceus Injection (AMI) on and mitochondrial function in chronic heart failure (CHF) based on phosphoproteomic and network pharmacology analysis. Primary neonatal mouse cardiomyocytes were isolated and hypertrophy cardiomyocyte model was induced by phenylephrine (PE) stimulation. AMI's effects on cell size, apoptosis, mitophagy, and mitochondrial function in hypertrophic cardiomyocytes were assessed. A pressure-overload CHF model was established via transverse aortic constriction (TAC) surgery in C57BL/6N mice. Echocardiography and histopathology were employed to evaluate AMI's effects on cardiac function and structural remodeling. Transmission electron microscope (TEM) and immunofluorescence were used to detect the distribution of autophagosomes and mitochondria. Phosphorylation-antibody microarray and network pharmacology were employed to explore AMI's cardioprotective mechanisms. The 's involvement was verified through Western blotting of AKTand mTORphosphorylation and pharmacological validation using SC79 (AKT/mTOR activator) and GSK-690693 (AKT/mTOR inhibitor) in gain/loss-of-function experiments. In vitro, AMI dose-dependently suppressed pathological hypertrophy, attenuated apoptosis, restored mitochondrial function, and enhanced mitophagic flux. In vivo, AMI treatment significantly improved left ventricular ejection fraction while attenuated cardiac hypertrophy and interstitial fibrosis in TAC-induced CHF mice. Besides, AMI treatment increased the number of mitochondria and elevated autophagy in TAC mice. Phosphoproteomic screening and network pharmacology analysis identified the PI3K/AKT/mTOR axis as the primary regulatory pathway mediating AMI's cardioprotection. Pharmacological activation of AKT/mTOR signaling using SC79 significantly suppressed mitophagic flux, whereas AMI treatment mirrored the effects of the AKT/mTOR inhibitor GSK-690693, effectively restoring mitophagy and mitochondrial homeostasis. AMI exerts its cardioprotective effects through inhibition of the AKT/mTOR pathway, thereby ameliorating maladaptive remodeling and mitochondrial dysfunction in CHF. Ser473Ser2481
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