中国科学技术大学Jian-ping Weng，Li-qin Tang和Suo-wen Xu共同合作，近期取得重要工作进展。他们研究提出，恩格列净和利拉鲁肽通过增强Erbb4信号通路改善小鼠的射血分数保留型心力衰竭（HFpEF）。相关研究成果2024年4月8日在线发表于《中国药理学报》杂志上。

据介绍，射血分数保留型心力衰竭（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，但其潜在机制尚不清楚。

研究人员在HFpEF小鼠模型中探讨了empagliflozin（恩格列净）和liraglutide（利拉鲁肽）的抗HFpEF作用及其潜在的分子机制。该模型采用高脂饮食（HFD）喂养加N^ω-硝基-L-精氨酸甲酯（L-NAME）处理建立。用恩格列净（20 mg·kg⁻¹·d⁻¹，i.g.）或利拉鲁肽（0.3 mg·kg⁻¹·d⁻¹，i.p.）或其组合持续处理4周。

在实验方案结束时，使用超声测量小鼠心脏功能，然后对小鼠实施安乐死，并收集心脏、肝脏和肾脏组织。从冷冻的小鼠心室组织中分离细胞核进行单核RNA测序（snRNA-seq）。研究人员发现，恩格列净或利拉鲁肽单独或联合用药显著改善了舒张功能，改善了心肌细胞肥大和心脏纤维化，以及运动耐受性，但在联合用药组中没有观察到协同作用。

此外，研究人员观察到恩格列净以及利拉鲁肽的处理降低了小鼠的体重和血压，改善了葡萄糖代谢和肝肾功能。停药1周后，这些有益作用趋于减弱。snRNA-seq分析揭示了一个肌细胞亚群，其中Erbb4的表达在HFpEF条件下下调，并通过恩格列净或利拉鲁肽恢复。拟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所必需的重要途径。在HFpEF小鼠模型中，恩格列净和利拉鲁肽都逆转了Erbb4的下调。在大鼠h9c2细胞中，研究人员发现棕榈酸或高糖至少部分通过Erbb4诱导PKCα以及ERK1/2磷酸化的变化。

总之，单细胞图谱揭示了恩格列净和利拉鲁肽的抗HFpEF机制，表明Erbb4途径代表了HFpEF的一个新的治疗靶点。

附：英文原文

Title: Empagliflozin and liraglutide ameliorate HFpEF in mice via augmenting the Erbb4 signaling pathway

Author: Ni, Xia-yun, Feng, Xiao-jun, Wang, Zhi-hua, Zhang, Yang, Little, Peter J., Cao, Yang, Xu, Suo-wen, Tang, Li-qin, Weng, Jian-ping

Issue&Volume: 2024-04-08

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 (20mg·kg1·d1, i.g.) or liraglutide (0.3mg·kg1·d1, 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.

DOI: 10.1038/s41401-024-01265-0

Source: https://www.nature.com/articles/s41401-024-01265-0