2. Academic Validation
  3. High-fat stimulation induces atrial structural remodeling via the TPM1/P53/SHISA5 Axis

High-fat stimulation induces atrial structural remodeling via the TPM1/P53/SHISA5 Axis

  • Lipids Health Dis. 2025 Apr 12;24(1):138. doi: 10.1186/s12944-025-02554-1.
Yansong Cui 1,  Shuting Bai 2,  Zhenlin Liu 2,  Haifeng Ding 1,  Kuan Li 3,  Zhan Li 4,  Yinglong Hou 5 6
Affiliations

Affiliations

  • 1 Department of Cardiology, Cheeloo College of Medicine, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
  • 2 Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Cardiac Electrophysiology and Arrhythmia, No. 16766, Jingshi Road, Jinan, Shandong Provincial, China.
  • 3 Clinical Medical Institute, Xinjiang Medical University, Urumqi, China.
  • 4 Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Cardiac Electrophysiology and Arrhythmia, No. 16766, Jingshi Road, Jinan, Shandong Provincial, China. zhanli1224@163.com.
  • 5 Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Cardiac Electrophysiology and Arrhythmia, No. 16766, Jingshi Road, Jinan, Shandong Provincial, China. yinglonghou@hotmail.com.
  • 6 Department of Cardiology, Cheeloo College of Medicine, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China. yinglonghou@hotmail.com.
PMID: 40221727 DOI: 10.1186/s12944-025-02554-1
Abstract

Background: Atrial structural remodeling plays a central role in the development and progression of atrial fibrillation (AF) and significantly influences its course. Hyperlipidemia, a potential contributor to AF, affects cardiac function through multiple pathways. This study aimed to investigate the underlying mechanisms by which high lipid levels promote AF progression.

Methods: In vitro cell models were established using palmitic acid (PA) stimulation, and in vivo rat models were generated by feeding a high-fat diet (HFD). Proteomic and transcriptomic Sequencing analyses were conducted to identify differentially expressed proteins and genes. Extracellular vesicles (EVs) were isolated and characterized by differential centrifugation. Cell proliferation was assessed using EdU incorporation and flow cytometry, while transmission electron microscopy (TEM) was used to observe Autophagy. Protein expression was analyzed by immunoblotting, immunohistochemistry, and immunofluorescence.

Results: High lipid stimulation significantly increased the expression of tropomyosin 1 (TPM1) in cardiomyocytes, which was transferred to cardiac fibroblasts via EVs, activating the P53/SHISA5 signaling axis and inducing endoplasmic reticulum (ER) stress and Autophagy, thereby promoting atrial structural remodeling. Activation of P53 and overexpression of SHISA5 in human cardiac fibroblast (HCF) cells reduced ER stress, Autophagy, and fibrosis. Furthermore, ER stress and Autophagy markers were significantly elevated in the atrial tissues of HFD-fed rats, while SHISA5 overexpression mitigated these effects.

Conclusion: High-fat stimulation may induce atrial fibrosis through the TPM1/P53/SHISA5 axis by modulating the ER stress-autophagy pathway.

Keywords

Atrial fibrillation; Autophagy; Endoplasmic reticulum stress; Extracellular vesicles; Saturated fatty acid; Structural remodeling.

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