Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Biochem Biophys Res Commun. 2021 Jun 4;556:207-214. doi: 10.1016/j.bbrc.2021.03.154. Epub 2021 Apr 10.
Bortezomib is a classical proteasome inhibitor and previous researches have reported its roles of anti-oxidation and anti-inflammatory functions in various diseases. However, the role of Bortezomib in myocardial ischemia reperfusion injury (MIRI) is unclear. Thus, our research seeks to reveal the protective effects of Bortezomib pretreatment in the mice model of MIRI. First, by the optimization of Bortezomib concentration and pretreatment timepoints, we found that 0.5 mg/kg Bortezomib pretreatment 2 h before MIRI significantly attenuated pathological damage and neutrophil infiltration. Then we found that pretreatment with Bortezomib obviously increased myocardial systolic function ((left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS)) and decreased infarct size, as well as serum Troponin T levels. Meanwhile, Bortezomib pretreatment also remarkably augmented oxidative stress related protein levels of Superoxide dismutase [Cu-Zn] (SOD1), Catalase (CAT) and Glutathione (GSH), while reactive oxygen species (ROS) contents and Malonaldehyde (MDA) protein level were significantly reduced. Mechanistically, Bortezomib pretreatment significantly promoted nuclear translocation of transcriptional factor nuclear factor erythroid 2-related factor 2(Nrf2) and Heme Oxygenase 1(HO-1) expression. Interestingly, co-treatment with ML-385, a new type and selective Nrf2 inhibitor, counteracted antioxidative effects induced by Bortezomib pretreatment. In conclusion, Bortezomib pretreatment mitigates MIRI by inhibiting oxidative damage which is regulated by Nrf2/HO-1 signaling pathway.
硼替佐米是一种经典的蛋白酶体抑制剂，先前的研究报道了其在各种疾病中的抗氧化和抗炎作用。然而，硼替佐米在心肌缺血再灌注损伤（MIRI）中的作用尚不清楚。因此，我们的研究旨在揭示硼替佐米预处理在 MIRI 小鼠模型中的保护作用。首先，通过优化硼替佐米浓度和预处理时间点，我们发现 0.5mg/kg 硼替佐米在 MIRI 前 2 小时预处理可显著减轻病理损伤和中性粒细胞浸润。然后我们发现，硼替佐米预处理明显增加了心肌收缩功能（（左心室射血分数（LVEF）和左心室缩短分数（LVFS））并减少了梗塞面积，以及血清肌钙蛋白 T 水平。同时，硼替佐米预处理还显著增加了超氧化物歧化酶[Cu-Zn]（SOD1）、过氧化氢酶（CAT）和谷胱甘肽（GSH）等氧化应激相关蛋白水平，而活性氧（ROS）含量和丙二醛（MDA）蛋白水平则显著降低。在机制上，硼替佐米预处理显著促进了转录因子核因子红细胞 2 相关因子 2（Nrf2）和血红素加氧酶 1（HO-1）的核转位和表达。有趣的是，用新型和选择性 Nrf2 抑制剂 ML-385 共同处理，抵消了硼替佐米预处理诱导的抗氧化作用。总之，硼替佐米预处理通过抑制氧化损伤减轻 MIRI，而氧化损伤是由 Nrf2/HO-1 信号通路调节的。
