期刊
ANTIOXIDANTS
卷 11, 期 11, 页码 -出版社
MDPI
DOI: 10.3390/antiox11112210
关键词
volume overload; hypertrophy; oxidative stress; heat shock proteins; protein quality control
资金
- EU's Horizon 2020 research and innovation program [739593]
- DFG (Deutsche Forschungsgemeinschaft) [HA 7512/2-4, HA 7512/2-1]
- NRDI Fund [2019-1.1.1-PIACI-KFI-2019-00367]
- Thematic Excellence Programme [2020-4.1.1.-TKP2020]
- New National Excellence Program [UNKP-22-5-SZTE-542]
- Hungarian Academy of Sciences [bo_481_21]
- EMBO [8792]
- Heinrich und Alma Vogelsang Stiftung
- German Academic Exchange Service (DAAD)
- European HCEMM [HU26307383]
- HungarianNational Scientific Research Fund [OTKA-138223, K139237]
- Hungarian National Cardiovascular Laboratory [RRF-2.3.1-21-2022-00003]
- Ministry for Innovation and Technology from the National Research, Development and Innovation Fund [KDP-2020]
This study investigates the effects of volume overload on the heart using a rat model and finds that it leads to cardiac hypertrophy, mechanical dysfunction, dysregulated signaling pathways, and increased oxidative stress. Furthermore, oxidative stress causes impairment of the protein quality control system.
Volume-induced hypertrophy is one of the risk factors for cardiac morbidity and mortality. In addition, mechanical and metabolic dysfunction, aging, and cellular redox balance are also contributing factors to the disease progression. In this study, we used volume overload (VO), which was induced by an aortocaval fistula in 2-month-old male Wistar rats, and sham-operated animals served as control. Functional parameters were measured by transthoracic echocardiography at termination 4- or 8-months after VO. The animals showed hypertrophic remodeling that was accompanied by mechanical dysfunction and increased cardiomyocyte stiffness. These alterations were reversible upon treatment with glutathione. Cardiomyocyte dysfunction was associated with elevated oxidative stress markers with unchanged inflammatory signaling pathways. In addition, we observed altered phosphorylation status of small heat shock proteins 27 and 70 and diminished protease expression caspases 3 compared to the matched control group, indicating an impaired protein quality control system. Such alterations might be attributed to the increased oxidative stress as anticipated from the enhanced titin oxidation, ubiquitination, and the elevation in oxidative stress markers. Our study showed an early pathological response to VO, which manifests in cardiomyocyte mechanical dysfunction and dysregulated signaling pathways associated with enhanced oxidative stress and an impaired protein quality control system.
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