Lingguizhugan decoction improves chronic heart failure by synergistically modulating β1-AR/Gs/GRKs/β-arrestin signaling bias

Lingguizhugan decoction (LGZG) is widely used in clinical practice for the treatment of various cardiovascular diseases to good effect. However, its specific mechanism of action remains unclear. This study aimed to investigate the potential mechanisms and effects of LGZG on isoproterenol (ISO) continuous stimulation-induced chronic heart failure (CHF) in mice and to provide direct experimental evidence for further clinical applications. In vivo, a continuous infusion of ISO was administered to mice, and ventricular myocytes were used to explore the potential mechanism of action of LGZG on the β1-adrenergic receptor (β1-AR)/Gs/G protein-coupled receptor kinases (GRKs)/β-arrestin signaling deflection system in the heart. We found that LGZG significantly reduced the mRNA expression of hypertrophy-related biomarkers (atrial natriuretic peptide, B-type natriuretic peptide) and improved cardiac remodeling and left ventricular diastolic function in mice with CHF induced by continuous ISO stimulation. Additionally, LGZG inhibited the overactivation of Gs/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling and further downregulated the downstream transcriptional activity of cAMP-response element binding protein and the expression of the coactivator CBP/P300. However, LGZG downregulated the expression of β-arrestin1 and G protein-coupled receptor kinase (GRK) 2/3/5 and upregulated the expression of β1-AR and β-arrestin2. Our results suggest that LGZG inhibits Gs/cAMP/PKA signaling and β-arrestin/GRK-mediated desensitization and internalization of β1-AR, which in turn may exert cardioprotective effects through the synergistic regulation of the β1-AR/Gs/GRKs/β-arrestin signaling deflection system via multiple pathways.