β2肾上腺素能受体(β2AR)是参与心脏保护的G蛋白偶联受体。在慢性心力衰竭(CHF)中,持续的交感神经系统激活,导致延长的β2AR激活和随后的受体脱敏和下调。三七皂苷R1(NGR1)具有增强心肌能量代谢和减轻心肌纤维化的作用。NGR1抗缺血性心力衰竭的机制尚不清楚。对C57BL/6J小鼠进行左前降支(LAD)动脉结扎操作4周。从第4周开始,他们用不同剂量(3,10,30mg/kg/天)的NGR1治疗。随后,通过评估心功能来评估NGR1对缺血性心力衰竭的影响,心脏组织的形态学变化,以及心房钠尿肽(ANP)和β-肌球蛋白重链(β-MHC)的表达。当暴露于OGD/R条件时,H9c2细胞被NGR1保护。H9c2细胞同样被NGR1保护免受OGD/R损伤。此外,NGR1增加β2AR水平,减少β2AR泛素化。机制研究表明,NGR1增强了MDM2蛋白的稳定性,并增加了MDM2和β-arrestin2的表达,同时抑制了它们的相互作用。此外,在OGD/R产生的条件下,给药MDM2抑制剂SP141后,NGR1对H9c2细胞的保护作用减弱.根据这些发现,NGR1阻碍β-arrestin2和MDM2之间的相互作用,从而阻止β2AR的泛素化和降解以改善CHF。
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.