Xinbao Pill attenuated chronic heart failure by suppressing the ubiquitination of β-adrenergic receptors.

BACKGROUD: Xinbao Pill (XBP) is extensively used in the adjuvant treatment of chronic heart failure in China. However, the pharmacological effect and underlying mechanism on CHF remains unclear.

PURPOSE: Our research was performed to investigate the cardioprotective effect of XBP against CHF and uncover the potential mechanism.

METHODS: Male Sprague-Dawley (SD) rats were subjected to the left anterior descending (LAD) artery ligation for 8 weeks and were treated with different doses of XBP (from the 4th week to the end). Cardiac function and morphology assessment were performed by using M-mode echocardiography, H&E and Masson staining. Western blotting analysis, co-immunoprecipitation (IP) assays, siRNA transfection were used to evaluate the mechanism of XBP.

RESULTS: XBP improved cardiac function and alleviated cardiac fibrosis in LAD-induced chronic heart failure rats. Meanwhile, XBP protected cardiomyocytes against oxygen-glucose deprivation (OGD) injury in AC16 cells and H9c2 cells. Additionally, XBP could increase the expression of β1 -AR and β2 -AR and inhibit their ubiquitanation. Further mechanism study showed that XBP upregulated USP18 expression, while silence of USP18 attenuated the cardioprotective effect of XBP and the increase of β1 -AR by XBP. Moreover, XBP increased MDM2 and β-arrestin2, and disrupted the interaction between Nedd4 and β2 -AR. After using the inhibitor of MDM2, SP141, the cardioprotective effect of XBP and the inhibitory effect on the ubiquitanation of β2 -AR were also blocked.

CONCLUSION: Our study firstly revealed that XBP improved cardiac function against CHF through suppressing USP18 and MDM2/β-arrestin2/Nedd4-mediated the ubiquitination of β1 -AR and β2 -AR.