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）作为一种肠道代谢物，在心力衰竭（heart failure, HF）小鼠体内水平显著升高。血浆中PAGln水平升高与心房颤动（atrial fibrillation, AF）相关，并参与AF的发病进程。然而，PAGln在合并心力衰竭的心房颤动中的作用仍不明确。因此本研究旨在探究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，造模周期为4周。于模型构建完成后，开展组织病理学检测、生化分析、超声心动图检查以评估心功能，并针对多项电生理指标（有效不应期effective refractory period, ERP、窦房结恢复时间sinus node recovery time, SNRT及心房颤动诱发率）进行电生理检测。 研究结果显示，PAGln干预的心力衰竭小鼠血浆PAGln水平显著升高；且PAGln可加重不良适应性结构重构与电重构，进而加剧心房颤动的易感性：缩短有效不应期时长、延长窦房结恢复时间，并提升心力衰竭小鼠的心房颤动诱发率。 机制层面分析表明，PAGln会加剧活性氧（reactive oxygen species, ROS）积累，并升高磷酸化受磷蛋白（phospholamban, PLB）与钙/钙调蛋白依赖性蛋白激酶II（calcium/calmodulin-dependent protein kinase II, CAMK II）的蛋白表达水平。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，发挥关键调控作用。