2. Academic Validation
  3. Inhibition of TREM-1 ameliorates angiotensin II-induced atrial fibrillation by attenuating macrophage infiltration and inflammation through the PI3K/AKT/FoxO3a signaling pathway

Inhibition of TREM-1 ameliorates angiotensin II-induced atrial fibrillation by attenuating macrophage infiltration and inflammation through the PI3K/AKT/FoxO3a signaling pathway

  • Cell Signal. 2024 Dec:124:111458. doi: 10.1016/j.cellsig.2024.111458.
Xin Chen 1,  Liming Yu 2,  Shan Meng 1,  Jikai Zhao 2,  Xinyi Huang 2,  Zhishang Wang 2,  Zijun Zhou 2,  Yuting Huang 2,  Tao Hong 3,  Jinfeng Duan 4,  Tong Su 5,  Zijun Cao 6,  Yanbang Chi 7,  Tao Huang 8,  Huishan Wang 9
Affiliations

Affiliations

  • 1 Postgraduate Training Base of General Hospital of Northern Theater Command, Jinzhou Medical University, Jinzhou, Liaoning 121001, PR China; State Key Laboratory of Frigid Zone Cardiovascular Disease, Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, PR China.
  • 2 State Key Laboratory of Frigid Zone Cardiovascular Disease, Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, PR China.
  • 3 State Key Laboratory of Frigid Zone Cardiovascular Disease, Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, PR China; Postgraduate College, Dalian Medical University, Dalian, Liaoning 116000, PR China; Pediatric Surgery Ward, Fuwai Hospital Chinese Academy of Medical Sciences, ShenZhen 518000, PR China.
  • 4 State Key Laboratory of Frigid Zone Cardiovascular Disease, Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, PR China; Postgraduate College, China Medical University, Shenyang, Liaoning 110122, PR China.
  • 5 State Key Laboratory of Frigid Zone Cardiovascular Disease, Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, PR China; College of Medicine and Biological Information Engineering, Northeastern University, Shenyang, Liaoning 110167, PR China.
  • 6 State Key Laboratory of Frigid Zone Cardiovascular Disease, Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, PR China; Postgraduate College, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 110847, PR China.
  • 7 State Key Laboratory of Frigid Zone Cardiovascular Disease, Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, PR China; Department of Obstetrics and Gynecology, General Hospital of Northern Theater Command, Shenyang 110016, PR China.
  • 8 State Key Laboratory of Frigid Zone Cardiovascular Disease, Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, PR China. Electronic address: huang_tao945@163.com.
  • 9 Postgraduate Training Base of General Hospital of Northern Theater Command, Jinzhou Medical University, Jinzhou, Liaoning 121001, PR China; State Key Laboratory of Frigid Zone Cardiovascular Disease, Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, PR China. Electronic address: huishanw@126.com.
PMID: 39384003 DOI: 10.1016/j.cellsig.2024.111458
Abstract

Inflammation and infiltration of immune cells are intricately linked to the pathogenesis of atrial fibrillation (AF). Triggering receptor expressed on myeloid cells-1 (TREM-1), an enhancer of inflammation, is implicated in various cardiovascular disorders. However, the precise role and potential mechanisms of TREM-1 in the development of AF remain ambiguous. Atrial samples from patients with AF were used to assess the expression levels of TREM-1. An angiotensin II (Ang II)-induced AF mouse model was established to assess the functionality of TREM-1. Cardiac function and AF inducibility were assessed through echocardiography, programmed transvenous cardiac pacing, and atrial electrophysiological mapping. Peripheral blood and atrial inflammatory cells were assessed using flow cytometry. Using histology, bulk RNA Sequencing, biochemical analyses, and cell cultures, the mechanistic role of TREM-1 in AF was elucidated. TREM-1 expression was upregulated and co-localized with macrophages in the atria of patients with AF. Pharmacological inhibition of TREM-1 decreased Ang II-induced atrial enlargement and electrical remodeling. TREM-1 inhibition also ameliorated Ang II-induced NLRP3 inflammasome activation, inflammatory factor release, atrial fibrosis, and macrophage infiltration. Transcriptomic analysis revealed that TREM-1 modulates Ang II-induced inflammation through the PI3K/Akt/FoxO3a signaling pathway. In vitro studies further supported these findings, demonstrating that TREM-1 activation exacerbates Ang II-induced inflammation, while overexpression of FoxO3a counteracts this effect. This study discovered the critical role of TREM-1 in the pathogenesis of AF and its underlying molecular mechanisms. Inhibition of TREM-1 provides a new therapeutic strategy for the treatment of AF.

Keywords

Angiotensin II; Atrial fibrillation; Inflammation; LR12; TREM-1.

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