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  3. Persistent hypertension induces atrial remodeling and atrial fibrillation through DNA damage and ATM/CHK2/p53 signaling pathway

Persistent hypertension induces atrial remodeling and atrial fibrillation through DNA damage and ATM/CHK2/p53 signaling pathway

  • Biochim Biophys Acta Mol Basis Dis. 2025 Jan;1871(1):167534. doi: 10.1016/j.bbadis.2024.167534.
Yuting Huang 1,  Jikai Zhao 1,  Zijun Zhou 1,  Xiaodong Guo 1,  Yinli Xu 1,  Tao Huang 1,  Shan Meng 2,  Zijun Cao 3,  Dengyue Xu 4,  Qiusheng Zhao 1,  Zongtao Yin 1,  Hui Jiang 1,  Liming Yu 5,  Huishan Wang 6
Affiliations

Affiliations

  • 1 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; Jinzhou Medical University, Jinzhou, Liaoning 121001, 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; Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 110847, 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; School of Biomedical Engineering, Faculty of Medicine, Dalian University of Technology, Dalian, Liaoning 116024, 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. Electronic address: lmyu2012@163.com.
  • 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. Electronic address: huishanw@126.com.
PMID: 39366645 DOI: 10.1016/j.bbadis.2024.167534
Abstract

Atrial fibrillation (AF) is the most prevalent arrhythmia in clinical practice, with hypertension emerging as an independent risk factor. Previous literature has established associations between DNA damage response (DDR) and Autophagy in relation to the pathogenesis of AF. The aim of this study was to evaluate the effect of atrial DNA damage response in persistent hypertension-induced atrial electrical and structural remodeling, and to further explore the potential therapeutic targets. Patient samples, spontaneous hypertensive rats (SHR) and angiotensin II (Ang II)-challenged HL-1 cells were employed to elucidate the detailed mechanisms. Bioinformatics analysis and investigation on human atrial samples revealed a critical role of DDR in the pathogenesis of AF. The markers of atrial DNA damage, DDR, Autophagy, inflammation and fibrosis were detected by western blot, immunofluorescence, monodansyl cadaverine (MDC) assay and transmission electron microscopy. Compared with the control group, SHR exhibited significant atrial electrical and structural remodeling, abnormal increase of Autophagy, inflammation, and fibrosis, which was accompanied by excessive activation of DDR mediated by the ATM/Chk2/p53 pathway. These detrimental changes were validated by in vitro experiments. Ang II-challenged HL-1 cells also exhibited significantly elevated γH2AX expression, and markers related to Autophagy, inflammation as well as structural remodeling. Additionally, inhibition of ATM with KU55933 (a specific ATM Inhibitor) significantly reversed these effects. Collectively, these data demonstrate that DNA damage and the subsequently overactivated ATM/Chk2/p53 pathway play critical roles in hypertension-induced atrial remodeling and the susceptibility to AF. Targeting ATM/Chk2/p53 signaling may serve as a potential therapeutic strategy against AF.

Keywords

ATM; Atrial fibrillation; Autophagy; DNA damage response; Inflammation.

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