PDF(Pubmed)
Abstract：
Heart failure with preserved ejection fraction (HFpEF) is closely associated with metabolic derangement. Sodium glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) exert anti-HFpEF effects, but the underlying mechanisms remain unclear. In this study, we explored the anti-HFpEF effects of empagliflozin and liraglutide and the underlying molecular mechanisms in a mouse model of HFpEF. This model was established by high-fat diet (HFD) feeding plus Nω-nitro-L-arginine methyl ester (L-NAME) treatment. The mice were treated with empagliflozin (20 mg·kg-1·d-1, i.g.) or liraglutide (0.3 mg·kg-1·d-1, i.p.) or their combination for 4 weeks. At the end of the experimental protocol, cardiac function was measured using ultrasound, then mice were euthanized and heart, liver, and kidney tissues were collected. Nuclei were isolated from frozen mouse ventricular tissue for single-nucleus RNA-sequencing (snRNA-seq). We showed that administration of empagliflozin or liraglutide alone or in combination significantly improved diastolic function, ameliorated cardiomyocyte hypertrophy and cardiac fibrosis, as well as exercise tolerance but no synergism was observed in the combination group. Furthermore, empagliflozin and/or liraglutide lowered body weight, improved glucose metabolism, lowered blood pressure, and improved liver and kidney function. After the withdrawal of empagliflozin or liraglutide for 1 week, these beneficial effects tended to diminish. The snRNA-seq analysis revealed a subcluster of myocytes, in which Erbb4 expression was down-regulated under HFpEF conditions, and restored by empagliflozin or liraglutide. Pseudo-time trajectory analysis and cell-to-cell communication studies confirmed that the Erbb4 pathway was a prominent pathway essential for both drug actions. In the HFpEF mouse model, both empagliflozin and liraglutide reversed Erbb4 down-regulation. In rat h9c2 cells, we showed that palmitic acid- or high glucose-induced changes in PKCα and/or ERK1/2 phosphorylation at least in part through Erbb4. Collectively, the single-cell atlas reveals the anti-HFpEF mechanism of empagliflozin and liraglutide, suggesting that Erbb4 pathway represents a new therapeutic target for HFpEF. Effects and mechanisms of action of empagliflozin and liraglutide in HFpEF mice. HFpEF was induced with a high-fat diet and L-NAME for 15 weeks, and treatment with empagliflozin and liraglutide improved the HFpEF phenotype. Single nucleus RNA sequencing (snRNA-seq) was used to reveal the underlying mechanism of action of empagliflozin and liraglutide.
摘要：
射血分数保留的心力衰竭（HFpEF）与代谢紊乱密切相关。钠葡萄糖协同转运蛋白-2抑制剂（SGLT2i）和胰高血糖素样肽-1受体激动剂（GLP-1RA）发挥抗HFpEF作用，但潜在的机制仍不清楚。在这项研究中,我们在HFpEF小鼠模型中探讨了依帕列净和利拉鲁肽的抗HFpEF作用以及潜在的分子机制.该模型是通过高脂饮食（HFD）喂养加Nω-硝基-L-精氨酸甲酯（L-NAME）处理建立的。用依帕列净（20mg·kg-1·d-1，i.g.）或利拉鲁肽（0.3mg·kg-1·d-1，i.p.）或其组合治疗4周。实验方案结束时,使用超声测量心脏功能，然后将小鼠安乐死并心脏，肝脏,并收集肾脏组织。从冷冻的小鼠心室组织中分离细胞核用于单核RNA测序(snRNA-seq)。我们表明，单独或联合使用依帕列净或利拉鲁肽可显著改善舒张功能，改善心肌细胞肥大和心脏纤维化，以及运动耐量，但在联合组中没有观察到协同作用。此外，empagliflozin和/或利拉鲁肽降低了体重，改善葡萄糖代谢，降低血压,改善肝肾功能.依帕列净或利拉鲁肽停药1周后，这些有益效果趋于减弱。snRNA-seq分析揭示了一个肌细胞亚簇，其中在HFpEF条件下Erbb4表达下调，并通过依帕列净或利拉鲁肽修复。伪时间轨迹分析和细胞间通讯研究证实，Erbb4途径是两种药物作用必不可少的重要途径。在HFpEF小鼠模型中，empagliflozin和利拉鲁肽均逆转了Erbb4的下调.在大鼠H9c2细胞中，我们表明，棕榈酸或高糖诱导的PKCα和/或ERK1/2磷酸化的变化至少部分通过Erbb4。总的来说，单细胞图谱揭示了依帕列净和利拉鲁肽的抗HFpEF机制，提示Erbb4通路代表了HFpEF的新治疗靶点。恩格列净和利拉鲁肽对HFpEF小鼠的作用及其机制。用高脂饮食和L-NAME诱导HFpEF15周，依帕列净和利拉鲁肽治疗可改善HFpEF表型。使用单核RNA测序（snRNA-seq）来揭示依帕列净和利拉鲁肽的潜在作用机制。
