Gömöri Kamilla, Herwig Melissa, Hassoun Roua, Budde Heidi, Mostafi Nusratul, Delalat Simin, Modi Suvasini, Begovic Merima, Szabados Tamara, Pipis Judit, Farkas-Morvay Nikolett, Leprán István, Kovács Árpád, Mügge Andreas, Ferdinandy Péter, Görbe Anikó, Bencsik Péter, Hamdani Nazha
Department of Cellular and Translational Physiology, Institute of Physiology, Ruhr University Bochum, 44801 Bochum, Germany.
Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany.
Antioxidants (Basel). 2022 Nov 8;11(11):2210. doi: 10.3390/antiox11112210.
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.
容量诱导的心肌肥厚是心脏发病和死亡的危险因素之一。此外，机械和代谢功能障碍、衰老以及细胞氧化还原平衡也是疾病进展的促成因素。在本研究中，我们对2月龄雄性Wistar大鼠采用主动脉腔静脉瘘诱导容量超负荷（VO），假手术动物作为对照。在VO后4个月或8个月处死时，通过经胸超声心动图测量功能参数。动物表现出肥厚性重塑，伴有机械功能障碍和心肌细胞僵硬度增加。用谷胱甘肽治疗后，这些改变是可逆的。心肌细胞功能障碍与氧化应激标志物升高相关，而炎症信号通路未改变。此外，与匹配的对照组相比，我们观察到小热休克蛋白27和70的磷酸化状态改变，半胱天冬酶3蛋白酶表达减少，表明蛋白质质量控制系统受损。这些改变可能归因于氧化应激增加，这是由肌联蛋白氧化、泛素化增强以及氧化应激标志物升高所预期的。我们的研究显示了对VO的早期病理反应，表现为心肌细胞机械功能障碍以及与氧化应激增强和蛋白质质量控制系统受损相关的信号通路失调。
