Ibrutinib-induced pulmonary angiotensin-converting enzyme activation promotes atrial fibrillation in rats
Sen Yan,
Wei Xu,
Ning Fang,
Luyifei Li,
Ning Yang,
Xinbo Zhao,
Hongting Hao,
Yun Zhang,
Qian Liang,
Zhiqi Wang,
Yu Duan,
Song Zhang,
Yongtai Gong,
Yue Li
Affiliations
Sen Yan
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Wei Xu
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Ning Fang
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Luyifei Li
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Ning Yang
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Xinbo Zhao
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Hongting Hao
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Yun Zhang
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Qian Liang
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Zhiqi Wang
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Yu Duan
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Song Zhang
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Yongtai Gong
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China; Corresponding author
Yue Li
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; Key Laboratory of Hepatosplenic Surgery, Harbin Medical University, Ministry of Education, Harbin 150001, China; Key Laboratory of Cardiac Diseases and Heart Failure, Harbin Medical University, Harbin 150001, China; Heilongjiang Key Laboratory for Metabolic Disorder & Cancer Related Cardiovascular Diseases, Harbin 150081, China; Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin, China; Corresponding author
Summary: 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.
