Clinical Laboratory, Women and Children's Health Care Hospital of Linyi, Linyi, Shandong, China.
Clinical Laboratory, Women and Children's Health Care Hospital of Gaoqing, Zibo, Shandong, China.
J Cardiovasc Pharmacol. 2021 Sep 12;78(6):839-846. doi: 10.1097/FJC.0000000000001138.
This study aims to investigate the effect and the related mechanisms of bromodomain-containing protein 4 (BRD4) inhibition on myocardial ischemia/reperfusion (I/R) injury. In vivo and in vitro myocardial I/R models were constructed. Expression of BRD4 was examined by RT-qPCR and Western blot. I/R injury was evaluated by analyzing cardiac function and the activity of biochemical markers of myocardial injury. Inflammation and oxidative stress were determined by measuring the levels of myeloperoxidase, TNF-α, IL-6, malondialdehyde, and superoxide dismutase. The activation of the PI3K/AKT signaling pathway was tested by the phosphorylation of p85 and AKT. We found BRD4 was significantly increased in the myocardial tissues after myocardial I/R injury. BRD4 inhibition suppressed the indices of cardiac function and the biochemical markers of myocardial injury. I/R-induced inflammation and oxidative stress were suppressed by shBRD4 in vivo and in vitro. In addition, BRD4 inhibition significantly increased the relative protein expression levels of p-p85, p-AKT T308, and p-AKT S473. In conclusion, this study for the first time demonstrated the protective effect of BRD4 inhibition on myocardial I/R injury in vivo and in vitro, and this effect was related to the suppression of inflammation and oxidative stress through the activation of the PI3K/AKT signaling pathway.
本研究旨在探讨溴结构域蛋白 4（BRD4）抑制对心肌缺血/再灌注（I/R）损伤的作用及相关机制。构建了体内和体外心肌 I/R 模型。通过 RT-qPCR 和 Western blot 检测 BRD4 的表达。通过分析心脏功能和心肌损伤生化标志物的活性来评估 I/R 损伤。通过测量髓过氧化物酶、TNF-α、IL-6、丙二醛和超氧化物歧化酶的水平来确定炎症和氧化应激。通过检测 p85 和 AKT 的磷酸化来测试 PI3K/AKT 信号通路的激活。我们发现，心肌 I/R 损伤后心肌组织中 BRD4 显著增加。BRD4 抑制抑制了心脏功能指标和心肌损伤的生化标志物。shBRD4 在体内和体外均抑制了 I/R 诱导的炎症和氧化应激。此外，BRD4 抑制显著增加了 p-p85、p-AKT T308 和 p-AKT S473 的相对蛋白表达水平。总之，本研究首次证明了 BRD4 抑制在体内和体外对心肌 I/R 损伤的保护作用，这种作用通过激活 PI3K/AKT 信号通路抑制炎症和氧化应激有关。
