Department of Cardiovascular Medicine, ZiBo First Hospital, Zibo, Shandong, 255200, China.
Department of Radiology, Shenzhen University General Hospital & Shenzhen University Clinical Medical Academy, Shenzhen, Guangdong, 518055, China.
Biomed Pharmacother. 2020 Jan;121:109368. doi: 10.1016/j.biopha.2019.109368. Epub 2019 Nov 25.
Hypertension is an essential regulator of cardiac injury and remodeling. However, the pathogenesis that contributes to cardiac hypertrophy remains to be fully explored. BRD4, as a bromodomain and extra-terminal (BET) family member, plays an important role in critical biological processes. In the study, our results showed that BRD4 expression was up-regulated in human and mouse hypertrophied hearts, and importantly these effects were modulated by reactive oxygen species (ROS) generation. In angiotensin II (Ang II)-treated cardiomyocytes, BRD4 decrease markedly blunted the prohypertrophic effect, which was further promoted by the combinational treatment of ROS scavenger (N-acetyl-cysteine, NAC). In addition, NAC pre-treatment markedly elevated the anti-fibrotic role of BRD4 suppression in Ang II-incubated cardiomyocytes by repressing transforming growth factor β1 (TGF-β1)/SMADs signaling pathway. NAC combined with BRD4 reduction further alleviated inflammation and oxidative stress in Ang II-exposed cardiomyocytes, which was partly through inhibiting nuclear factor-κB (NF-κB) signaling and improving nuclear erythroid factor 2-related factor 2 (Nrf-2)/heme oxygenase-1 (HO-1) pathway, respectively. Furthermore, the in vivo results confirmed the protective effects of BRD4 suppression on mice against aortic banding (AB)-induced cardiac hypertrophy, as evidenced by the reduced cross sectional area and fibrotic area using H&E and Masson trichrome staining. What's more, the degree of cardiac hypertrophy (ANP and BNP), the expression of pro-fibrotic genes (TGF-β1, Collagen I, Collagen III and CTGF), the levels of inflammation and oxidative stress were all significantly attenuated by the blockage of BRD4 in AB-operated mice. Taken together, repressing BRD4 expression was found to confer a protective effect against experimental cardiac hypertrophy in mice, demonstrating its potential as an effective therapeutic target for pathological cardiac hypertrophy.
高血压是心脏损伤和重塑的基本调节因子。然而，导致心脏肥大的发病机制仍有待充分探索。BRD4 作为溴结构域和末端（BET）家族成员，在关键的生物学过程中发挥着重要作用。在这项研究中，我们的结果表明 BRD4 在人类和小鼠肥大的心脏中表达上调，重要的是，这些效应是由活性氧（ROS）的产生调节的。在血管紧张素 II（Ang II）处理的心肌细胞中，BRD4 的减少明显削弱了促肥大作用，而 ROS 清除剂（N-乙酰半胱氨酸，NAC）的联合处理则进一步促进了这种作用。此外，NAC 预处理通过抑制转化生长因子 β1（TGF-β1）/SMADs 信号通路，显著增强了 BRD4 抑制在 Ang II 孵育的心肌细胞中的抗纤维化作用。NAC 与 BRD4 减少的联合作用进一步减轻了 Ang II 暴露的心肌细胞中的炎症和氧化应激，这部分是通过抑制核因子-κB（NF-κB）信号和改善核红细胞因子 2 相关因子 2（Nrf-2）/血红素加氧酶-1（HO-1）通路来实现的。此外，体内结果证实了 BRD4 抑制对小鼠主动脉缩窄（AB）诱导的心脏肥大的保护作用，通过 H&E 和 Masson 三色染色减少了横截面积和纤维化面积。更重要的是，心脏肥大的程度（ANP 和 BNP）、促纤维化基因（TGF-β1、胶原蛋白 I、胶原蛋白 III 和 CTGF）的表达、炎症和氧化应激的水平，在 AB 手术的小鼠中，BRD4 的阻断都显著减弱。总之，抑制 BRD4 的表达被发现对小鼠实验性心脏肥大具有保护作用，表明其作为病理性心脏肥大的有效治疗靶点具有潜力。
