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Modulation of the JNK/c-Jun/HSP27 pathway in cardiomyocytes under chronic stress-induced cardiac dysfunction:
Houyuan Zhou1, Jinfeng Yuan2, Xiaoying Chen2
1Department of Pharmacy, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Shanghai Key Laboratory of Compound Chinese Medicines, the Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, the MOE Innovation Centre for Basic Medicine Research on Qi-Blood TCM Theories, State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Insights
Depression-induced stress elevates corticosterone, causing cardiac oxidative damage. Tauroursodeoxycholic acid (TUDCA) protects the heart by modulating the JNK/c-Jun/HSP27 pathway, offering a potential therapy for depression-related cardiovascular issues.
Area of Science:
- Cardiology
- Neuroscience
- Biochemistry
Background:
- Depression elevates cardiovascular disease (CVD) risk via hypothalamic-pituitary-adrenal (HPA) axis hyperactivity and oxidative stress.
- Chronic unpredictable mild stress (CUMS) in mice models depression-like behaviors and HPA axis activation.
Purpose of the Study:
- To investigate how elevated corticosterone from CUMS impacts cardiac oxidative damage and dysfunction in mice.
- To evaluate the protective effects of tauroursodeoxycholic acid (TUDCA) against CUMS-induced cardiac pathology.
Main Methods:
- Mice subjected to CUMS exhibited electrocardiogram abnormalities, cardiac fibrosis, and elevated corticosterone.
- Assessed myocardial oxidative stress markers (ROS, SOD, GSH), apoptosis (BCL2/BAX ratio, TUNEL), and mitochondrial function.
- Utilized RNA-Seq to identify gene expression changes (Jun, Hspb1) and Western blotting for protein analysis (JNK/c-Jun, HSP27).
- In vitro studies used cortisol-treated AC-16 cells and specific pathway inhibitors/agonists (T-5224, Anisomycin).
Main Results:
- CUMS mice displayed cardiac dysfunction, increased myocardial oxidative stress, apoptosis, and mitochondrial damage.
- TUDCA treatment reversed these cardiac impairments, restoring redox balance and promoting cardiomyocyte survival.
- CUMS induced JNK/c-Jun activation and HSP27 suppression, which TUDCA counteracted.
- In vitro, TUDCA protected AC-16 cells from cortisol-induced damage, confirming the involvement of the JNK/c-Jun/HSP27 pathway.
Conclusions:
- Elevated corticosterone in depression contributes to cardiac dysfunction through oxidative stress and apoptosis.
- TUDCA mitigates depression-associated cardiac dysfunction by regulating the JNK/c-Jun/HSP27 signaling pathway.
- TUDCA presents a potential therapeutic strategy for managing cardiovascular complications in depression.
Aims:
Depression significantly increases the risk of cardiovascular diseases (CVD) by exacerbating hypothalamic-pituitary-adrenal (HPA) axis hyperactivity and oxidative stress damage, common risk factors for both conditions. Our study aims to elucidate how elevated corticosterone levels in mice induced by chronic unpredictable mild stress (CUMS), an experimental model showing depression-like behaviors, contribute to the cardiac oxidative damage and dysfunction, and to assess the protective role of tauroursodeoxycholic acid (TUDCA) in this process.
Results:
CUMS mice show electrocardiogram abnormalities, decreased cardiomyocyte size, increased perivascular fibrosis, and elevated circulating corticosterone. CUMS mice exhibit heightened oxidative stress in the left ventricular myocardium, evidenced by increased ROS levels and decreased SOD, GSH levels, and fewer mitochondria with evidence of damage. This oxidative imbalance is accompanied by a reduced BCL2/BAX protein ratio and a higher percentage of TUNEL+ cardiomyocytes, confirming myocardial apoptosis. TUDCA treatment reverses these effects, restoring redox balance and cardiomyocyte survival. RNA-Seq reveals downregulated Jun and Hspb1 genes involved in oxidative stress, while JNK/c-Jun activation and HSP27 suppression in CUMS mice, TUDCA treatment reverses these proteins change. In vitro, TUDCA reverses the reduced AC-16 cell viability and mitochondrial function, increases ROS levels, and decreases SOD and GSH levels induced by cortisol. Treatment with c-Jun inhibitor T-5224 and JNK agonist Anisomycin confirms cortisol's activation of JNK/c-Jun signaling, inhibition of HSP27 expression, and reduction of SOD and GSH levels, all of which are counteracted by TUDCA.
Conclusion:
Elevated corticosterone levels in depression contribute to cardiac dysfunction through oxidative damage. TUDCA mitigates these effects via the JNK/c-Jun/HSP27 pathway, which offers potential therapeutic implications for depression-associated cardiac dysfunction.
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