Notoginsenoside R1 attenuates ischemic heart failure by modulating MDM2/β arrestin2-mediated β2-adrenergic receptor...

β2 adrenergic receptor (β2AR) is a G-protein-coupled receptor involved in cardiac protection. In chronic heart failure (CHF), persistent sympathetic nervous system activation occurs, resulting in prolonged β2AR activation and subsequent receptor desensitization and downregulation. Notoginsenoside R1 (NGR1) has the functions of enhancing myocardial energy metabolism and mitigating myocardial fibrosis. The mechanisms of NGR1 against ischemic heart failure are unclear. A left anterior descending (LAD) artery ligation procedure was performed on C57BL/6 J mice for four weeks. From the 4th week onwards, they were treated with various doses (3, 10, 30 mg/kg/day) of NGR1. Subsequently, the impacts of NGR1 on ischemic heart failure were evaluated by assessing cardiac function, morphological changes in cardiac tissue, and the expression of atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC). H9c2 cells were protected by NGR1 when exposed to OGD/R conditions. H9c2 cells were likewise protected from OGD/R damage by NGR1. Furthermore, NGR1 increased β2AR levels and decreased β2AR ubiquitination. Mechanistic studies revealed that NGR1 enhanced MDM2 protein stability and increased the expression of MDM2 and β-arrestin2 while inhibiting their interaction. Additionally, under conditions produced by OGD/R, the protective benefits of NGR1 on H9c2 cells were attenuated upon administration of the MDM2 inhibitor SP141. According to these findings, NGR1 impedes the interplay between β-arrestin2 and MDM2, thereby preventing the ubiquitination and degradation of β2AR to improve CHF.