Astragaloside IV Alleviates Heart Failure by Modulating Nrf-2
Heart failure (HF) is a global health concern affecting approximately 1%–2% of adults worldwide. The condition arises from various causes, including valvular heart diseases, chronic or acute cardiac ischemia, and cardiomyopathies induced by factors such as alcohol, doxorubicin (Dox), hypertension, diabetes, and metabolic syndrome. Despite advancements in therapeutic approaches, effective treatments for HF remain limited, necessitating the development of more practical strategies and therapeutic candidates. Astragaloside IV (AS-IV), a principle active constituent of Astragalus membranaceus Bunge, has shown promise in alleviating HF. This article explores the mechanisms by which AS-IV exerts its cardioprotective effects, focusing on its modulation of nuclear factor erythroid 2-related factor 2 (Nrf-2) signaling.
The study utilized a Wistar rat model to investigate the effects of AS-IV on HF induced by Dox. Male Wistar rats, aged three months and weighing 180–200 g, were randomly assigned to three groups: a sham group, a Dox-treated HF group, and a Dox-treated HF group receiving AS-IV. HF was induced by intraperitoneal injection of Dox (3 mg/kg, twice weekly for six weeks), while the sham group received an equal volume of saline. After one week of Dox injections, AS-IV (1.0 mg/kg) was administered intraperitoneally daily, with saline serving as the control. Echocardiography was performed at nine weeks to assess cardiac function, revealing a significant decrease in left ventricular ejection fraction (EF) in the HF group compared to the sham group. AS-IV treatment notably increased EF levels, indicating improved cardiac function.
Histological analysis using wheat germ agglutinin (WGA) staining demonstrated that Dox treatment resulted in enlarged cardiomyocytes, a phenotype mitigated by AS-IV. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining revealed increased apoptosis in the hearts of HF rats, which was significantly reduced by AS-IV treatment. Western blot analysis showed that Dox treatment upregulated dynamin-related protein 1 (DRP1) expression while downregulating mitofusin1 and mitofusin2, changes that were reversed by AS-IV. Additionally, AS-IV rescued the HF-impaired expression of Nrf-2 and its downstream gene heme oxygenase-1 (HO-1), suggesting a role for Nrf-2/HO-1 signaling in the cardioprotective effects of AS-IV.
In vitro studies using the H9C2 cell line further supported these findings. H9C2 cells were treated with Dox (1 mmol/L) alone or in combination with AS-IV (low dose: 50 mmol/L or high dose: 100 mmol/L) for 24 hours. Dox treatment significantly promoted apoptosis and necrosis in H9C2 cells, effects that were reversed by AS-IV in a dose-dependent manner. Flow cytometry analysis using JC-1 fluorescence revealed that Dox treatment increased the percentage of cells with low membrane potential, a phenotype attenuated by AS-IV. Western blot analysis confirmed that Dox upregulated DRP1 expression while downregulating mitofusin1 and mitofusin2, changes that were reversed by AS-IV. Moreover, AS-IV partially rescued the Dox-impaired expression of Nrf-2 and HO-1 in H9C2 cells.
The study concludes that AS-IV exerts cardioprotective effects against HF by modulating Nrf-2 signaling. AS-IV attenuates Dox-induced cardiomyocyte apoptosis and mitochondrial dysfunction, providing molecular evidence for its therapeutic value in HF progression. These findings suggest that AS-IV may alleviate Dox-induced cardiotoxicity during Dox-dependent antitumor therapy, offering a potential therapeutic strategy for HF patients.
The research was supported by grants from the National Natural Science Foundation of China, highlighting the significance of this work in advancing our understanding of HF and its treatment. The findings underscore the potential of AS-IV as a therapeutic candidate, paving the way for further clinical investigations and applications.
doi.org/10.1097/CM9.0000000000001828
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