Effects of Phenylacetylglutamine on the Overpressure-Induced HF Mice

Phenylacetylglutamine (PAGln), a gut metabolite is substantially elevated in heart failure (HF). The increase of PAGln in plasma is associated with atrial fibrillation (AF), and contributes to AF pathogenesis. However, the role of PAGln in AF with HF remains uncertain. Therefore, this study aimed to determine the effect of PAGln on AF after HF. Thoracic aortic coarctation (TAC) created overpressure-induced HF mice for 4 weeks. Histopathology, biochemical, echocardiographic for assessment of cardiac function, and electrophysiological examination of several electrophysiological indexes (ERP, SNRT, and the occurrence rate of AF) were performed at the end of the HF mice model. We found that plasma PAGln levels were significantly elevated in PAGln-treated HF mice and that PAGln aggravated maladaptive structural remodeling and electrical remodeling, which aggravated the vulnerability of AF, shortened the ERP duration, prolonged the SNRT, increased the occurrence rate of AF in HF mice. Mechanistically, PAGln exacerbated ROS accumulation and increased the levels of phosphorylated PLB and CAMK II. Overall, PAGln played a vital role in promoting the occurrence of AF in HF mice by activating the CAMK II signaling pathway.

苯乙酰谷氨酰胺（Phenylacetylglutamine, PAGln）是一种肠道代谢物，在心力衰竭（heart failure, HF）患者体内水平显著升高。血浆PAGln水平升高与心房颤动（atrial fibrillation, AF）相关，并参与AF的发病机制。然而，PAGln在合并心力衰竭的心房颤动中的作用仍不明确。因此，本研究旨在探讨PAGln对心力衰竭后心房颤动的影响。本研究通过胸主动脉缩窄（thoracic aortic coarctation, TAC）构建压力超负荷诱导的心力衰竭小鼠模型，造模时长为4周。于心力衰竭小鼠模型造模完成后，开展组织病理学检测、生化指标分析、超声心动图心功能评估，以及针对多项电生理指标（ERP、SNRT及AF发生率）的电生理检查。结果显示，PAGln干预组心力衰竭小鼠的血浆PAGln水平显著升高；PAGln可加重不良结构重构与电重构，进而加剧心房颤动的易感性，同时缩短ERP时长、延长SNRT，并升高心力衰竭小鼠的AF发生率。机制研究表明，PAGln可加剧活性氧（Reactive Oxygen Species, ROS）积累，并提升磷酸化PLB与CAMK II的蛋白水平。综上，PAGln可通过激活CAMK II信号通路，在心力衰竭小鼠中促进心房颤动的发生，发挥关键致病作用。