Astragaloside IV alleviates heart failure by restoring gut microbiota-derived short-chain fatty acids and suppressing HDAC1/2/3.

BACKGROUND

The interaction between Astragaloside IV (AS-IV) and the gut microbiota is known to help prevent cardiovascular disease, however, its underlying mechanism through which AS-IV modulates the balance of intestinal flora to ameliorate heart failure (HF) remains unclear.

METHODS

A rat HF model was created using coronary artery ligation to study AS-IV's cardioprotective effects, while an AngII-activated H9c2 hypertrophy model assessed AS-IV's impact on cellular hypertrophy. AS-IV's therapeutic effects were evaluated through histopathology, 16S rRNA sequencing, SCFA-targeted omics, and HDAC molecular assays.

RESULTS

AS-IV markedly enhanced cardiac function in HF rats. AS-IV treatment ameliorated gut microbiota dysbiosis in HF rats. AS-IV also altered short-chain fatty acid (SCFA) levels, leading to an increase in hexanoic, heptanoic, octanoic, decanoic, valeric, pentanoic, acetic, propionic, nonanoic, isobutyric, and isovaleric acids. Additionally, AS-IV concurrently suppressed the overexpression of HDAC1, HDAC2, and HDAC3 in both HF rats and H9c2 cells, alleviated myocardial fibrosis, and reduced cardiomyocyte hypertrophy.

CONCLUSIONS

AS-IV exerts its therapeutic effects against HF through a multifaceted mechanism involving the amelioration of gut dysbiosis, enrichment of SCFA-producing bacteria, restoration of SCFA levels, and suppression of HDAC1/2/3 expression.