DOI: 10.1161/jaha.125.045604 ISSN: 2047-9980

Chronic Pain Synergizes With High‐Fat Diet to Promote Cardiac Injury via c‐Jun N‐Terminal Kinase 1/Silent Information Regulator 1 Signaling Axis in Apolipoprotein E‐Deficient Mice

Lan Wei, Qiang Tao, Shan You, Yi Zhang, Lianhua Chen, Ming Lian, Lina Huang, Chao Gong
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Background

Both hyperlipidemia and chronic pain were recognized risk factors for cardiac injury, which could lead to cardiovascular diseases.

Methods

Thirty‐two male APOE−/− (apolipoprotein E‐deficient) mice (C57BL/6 background, 1 month old) were randomly allocated to 4 groups (n=8/group): Sham group: high‐fat diet+sham surgery for 3 months; P1 to P3 groups: high‐fat diet +spared nerve injury‐induced chronic pain initiated at 1, 2, or 3 months post high‐fat diet commencement, respectively. Mechanical allodynia was induced via the spared nerve injury model. Pain thresholds were quantified using von Frey filaments. Anxiety‐like behaviors were assessed via the Open Field Test. Transthoracic echocardiography was performed to measure left ventricular ejection fraction and fractional shortening. Serum biomarkers of myocardial injury, inflammatory cytokines and lipid profiles were analyzed by ELISA. Myocardial tissue sections were subjected to histopathological staining, immunohistochemistry, immunofluorescence, and Western blotting.

Results

Chronic pain exerted negligible effects on high‐fat diet‐induced metabolic dysregulation, as evidenced by comparable levels of total cholesterol, low‐density lipoprotein cholesterol, and triglycerides across all groups ( P >0.05). In contrast, mice subjected to chronic pain (P1–P3 groups) exhibited significant deterioration in myocardial contractility, exacerbated fibrosis and collagen deposition, elevated cardiac injury biomarkers, and pronounced inflammatory cell infiltration compared with Sham group. These alterations correlated with dysregulated JNK1 (c‐Jun N‐terminal kinase 1) activation and suppressed Sirt1 (silent information regulator 1) expression in myocardial tissues.

Conclusions

These findings demonstrated that chronic pain synergistically exacerbated hyperlipidemia‐induced cardiac injury, primarily mediated through inflammatory mechanisms and JNK1/Sirt1 signaling dysregulation.

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