Liu Peng, Wang Lu, Wang Yixin, Jin Linyan, Gong Haoyu, Fan Jiali, Zhang Yudi, Li Haiquan, Fu Bowen, Wang Qiaozhu, Fu Yuping, Fan Boyuan, Li Xiaoli, Wang Hongtao, Qin Xinghua, Zheng Qiangsun
Department of Cardiology, The Second Affiliate Hospital of Xi'an Jiaotong University, No.157, Xiwu Road, Xincheng District, Xi'an, 710004, Shaanxi, China.
Department of Endocrinology, The First Affiliate Hospital of Xi'an Jiaotong University, Xi'an, China.
Cardiovasc Diabetol. 2024 Dec 21;23(1):452. doi: 10.1186/s12933-024-02545-z.
Atrial fibrillation (AF) is the most prevalent arrhythmia in clinical practice, and obesity serves as a significant risk factor for its development. The underlying mechanisms of obesity-related AF remain intricate and have yet to be fully elucidated. We have identified FPR2 as a potential hub gene involved in obesity-related AF through comprehensive analysis of four transcriptome datasets from AF patients and one transcriptome dataset from obese individuals, and its expression is up-regulated in both AF and obese individuals. Interestingly, ANXA1, the endogenous ligand of FPR2, was found to exhibit differential expression with AF and obesity. Specifically, it was observed to be down-regulated in AF patients but up-regulated in obese individuals. The susceptibility to AF in obese mice induced by high-fat diet (HFD) was increased following with the FPR2 blocker Boc-2.The administration of exogenous ANXA1 active peptide chain Ac2-26 can mitigate the susceptibility to AF in obese mice by attenuating atrial fibrosis, lipid deposition, oxidative stress injury, and myocardial cell apoptosis. However, this protective effect against AF susceptibility is reversed by AAV9-shAMPK-mediated AMPK specific knockdown in the myocardium. The vitro experiments demonstrated that silencing ANXA1 exacerbated lipid deposition, oxidative stress injury, and apoptosis induced by palmitic acid (PA) in cardiomyocytes. Additionally, Ac2-26 effectively mitigated myocardial lipid deposition, oxidative stress injury, and apoptosis induced by PA. These effects were impeded by FPR2 inhibitors Boc-2 and WRW4. The main mechanism involves the activation of AMPK by ANXA1 through FPR2 in order to enhance fatty acid oxidation in cardiomyocytes, thereby ultimately leading to a reduction in lipid accumulation and associated lipotoxicity. Our findings demonstrate that the ANXA1-FPR2 axis plays a protective role in obesity-associated AF by alleviating metabolic stress in the atria of obese mice, thereby emphasizing its potential as a promising therapeutic target for AF.
心房颤动（AF）是临床实践中最常见的心律失常，肥胖是其发生的重要危险因素。肥胖相关性房颤的潜在机制仍然复杂，尚未完全阐明。通过对房颤患者的四个转录组数据集和肥胖个体的一个转录组数据集进行综合分析，我们确定FPR2是参与肥胖相关性房颤的一个潜在枢纽基因，其在房颤患者和肥胖个体中均上调表达。有趣的是，FPR2的内源性配体ANXA1在房颤和肥胖中表现出差异表达。具体而言，在房颤患者中观察到其表达下调，而在肥胖个体中上调。高脂饮食（HFD）诱导的肥胖小鼠对房颤的易感性在使用FPR2阻滞剂Boc-2后增加。外源性ANXA1活性肽链Ac2-26的给药可通过减轻心房纤维化、脂质沉积、氧化应激损伤和心肌细胞凋亡来减轻肥胖小鼠对房颤的易感性。然而，心肌中AAV9-shAMPK介导的AMPK特异性敲低可逆转这种对房颤易感性的保护作用。体外实验表明，沉默ANXA1会加剧棕榈酸（PA）诱导的心肌细胞脂质沉积、氧化应激损伤和凋亡。此外，Ac2-26有效减轻了PA诱导的心肌脂质沉积、氧化应激损伤和凋亡。这些作用被FPR2抑制剂Boc-2和WRW4所阻断。主要机制涉及ANXA1通过FPR2激活AMPK，以增强心肌细胞中的脂肪酸氧化，从而最终导致脂质积累和相关脂毒性的减少。我们的研究结果表明，ANXA1-FPR2轴通过减轻肥胖小鼠心房的代谢应激，在肥胖相关性房颤中发挥保护作用，从而强调了其作为房颤有前景的治疗靶点的潜力。
