Shuai Wei, Peng Bo, Zhu Jun, Kong Bin, Fu Hui, Huang He
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, PR China.
Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, Hubei, PR China.
Heliyon. 2023 Aug 29;9(9):e19501. doi: 10.1016/j.heliyon.2023.e19501. eCollection 2023 Sep.
Ibrutinib is an effective and well-tolerated treatment for B-cell lymphomas but is associated with an increased risk of atrial fibrillation (AF) by altering the structure of the atrium. 5-Methoxytryptophan (5-MTP) inhibits inflammatory and fibrotic processes. This study aimed to determine the effects and mechanisms of 5-MTP on the underlying mechanisms of AF caused by ibrutinib.
The effect of 5-MTP on ibrutinib-related AF was investigated in male Sprague Dawley rats using echocardiographic, electrophysiological, immunofluorescent, Masson staining, and molecular analyses.
The ibrutinib+5-MTP group showed (1) a lower incidence and shorter duration of AF and accelerated atrial conduction; (2) a decreased left atrial mass and left atrial diameter; (3) decreased myocardial fibrosis in the left atrium; (4) lower atrial inflammation; (5) increased sarcoplasmic reticulum Ca-ATPase 2a protein expression, decreased phosphorylation of phospholamban at Thr17, and decreased sodium/calcium exchanger 1 protein expression and phosphorylation of ryanodine receptor 2 at S2814; and (6) decreased phosphorylation of CaMKII expression. 5-MTP treatment markedly activated the PI3K-Akt signaling. Inhibiting PI3K-Akt signaling significantly reversed the protective effect of 5-MTP on ibrutinib-related AF.
These findings suggest that 5-MTP administration decreases the vulnerability of ibrutinib-related AF mainly caused by ameliorated maladaptive left atrial remodeling and dysregulation of calcium handling proteins. Mechanistically, 5-MTP treatment markedly enhanced the activation of cardiac PI3K-Akt signaling.
依鲁替尼是治疗B细胞淋巴瘤的一种有效且耐受性良好的药物，但通过改变心房结构会增加心房颤动（AF）的风险。5-甲氧基色氨酸（5-MTP）可抑制炎症和纤维化过程。本研究旨在确定5-MTP对依鲁替尼所致AF潜在机制的影响及作用机制。
使用超声心动图、电生理学、免疫荧光、Masson染色和分子分析，在雄性Sprague Dawley大鼠中研究5-MTP对依鲁替尼相关AF的影响。
依鲁替尼+5-MTP组表现出：（1）AF发生率较低、持续时间较短且心房传导加速；（2）左心房质量和左心房直径减小；（3）左心房心肌纤维化减轻；（4）心房炎症减轻；（5）肌浆网Ca-ATP酶2a蛋白表达增加，受磷蛋白在苏氨酸17位点的磷酸化减少，钠/钙交换体1蛋白表达减少，兰尼碱受体2在丝氨酸2814位点的磷酸化减少；（6）CaMKII表达的磷酸化减少。5-MTP治疗显著激活了PI3K-Akt信号通路。抑制PI3K-Akt信号通路可显著逆转5-MTP对依鲁替尼相关AF的保护作用。
这些发现表明，给予5-MTP可降低依鲁替尼相关AF的易感性，这主要是通过改善适应性不良的左心房重构和钙处理蛋白的失调实现的。从机制上讲，5-MTP治疗显著增强了心脏PI3K-Akt信号通路的激活。
