Yan Sen, Xu Wei, Fang Ning, Li Luyifei, Yang Ning, Zhao Xinbo, Hao Hongting, Zhang Yun, Liang Qian, Wang Zhiqi, Duan Yu, Zhang Song, Gong Yongtai, Li Yue
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China.
NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Heilongjiang 150001, China.
iScience. 2024 Jan 17;27(2):108926. doi: 10.1016/j.isci.2024.108926. eCollection 2024 Feb 16.
The molecular mechanism of ibrutinib-induced atrial fibrillation (AF) remains unclear. We here demonstrate that treating rats with ibrutinib for 4 weeks resulted in the development of inducible AF, left atrial enlargement, atrial fibrosis, and downregulation of connexin expression, which were associated with C-terminal Src kinase (CSK) inhibition and Src activation. Ibrutinib upregulated angiotensin-converting enzyme (ACE) protein expression in human pulmonary microvascular endothelial cells (HPMECs) by inhibiting the PI3K-AKT pathway, subsequently increasing circulating angiotensin II (Ang II) levels. However, the expression of ACE and Ang II in the left atria was not affected. Importantly, we observed that perindopril significantly mitigated ibrutinib-induced left atrial remodeling and AF promotion by inhibiting the activation of the ACE and its downstream CSK-Src signaling pathway. These findings indicate that the Ibrutinib-induced activation of the ACE contributes to AF development and could serve as a novel target for potential prevention strategies.
依鲁替尼诱发心房颤动（AF）的分子机制尚不清楚。我们在此证明，用依鲁替尼治疗大鼠4周会导致可诱导性AF的发生、左心房扩大、心房纤维化以及连接蛋白表达下调，这些都与C末端Src激酶（CSK）抑制和Src激活有关。依鲁替尼通过抑制PI3K-AKT途径上调人肺微血管内皮细胞（HPMECs）中血管紧张素转换酶（ACE）蛋白表达，随后增加循环血管紧张素II（Ang II）水平。然而，左心房中ACE和Ang II的表达未受影响。重要的是，我们观察到培哚普利通过抑制ACE及其下游CSK-Src信号通路的激活，显著减轻了依鲁替尼诱导的左心房重塑和AF进展。这些发现表明，依鲁替尼诱导的ACE激活促成了AF的发展，并可作为潜在预防策略的新靶点。
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