Inhibition of BET bromodomain attenuates angiotensin II induced abdominal aortic aneurysm in ApoE-/- mice
Inhibition of BET bromodomain attenuates angiotensin II induced abdominal aortic aneurysm in ApoE-/- mice
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BET 溴结构域的抑制可减轻血管紧张素 II 诱导的 ApoE(-/-) 小鼠腹主动脉瘤
DOI：
10.1016/j.ijcard.2016.08.238
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发表时间：
2016-11-15
影响因子：
3.5
通讯作者：
Yang, Tianlun
中科院分区：
文献类型：
--
作者：
Duan, Qiong;Mao, Xiaoxiao;Yang, Tianlun
背景资料：基质金属蛋白酶（MMP）过度降解细胞外基质是腹主动脉瘤（AAA）的主要病理特征。在临床前模型中，细胞外基质降解的抑制减弱了AAA的发生和进展。在本研究中，我们想要测试JQ 1（一种选择性靶向溴结构域和末端外结构域（BET）的小化学分子）对ApoE（-/-）小鼠中AngII诱导的AAA形成的影响。为了研究BET布罗莫结构域在AAA发病机制中的作用，将雄性ApoE-/-小鼠输注血管紧张素II，（AngII，1000 ng/kg/min）持续21天，并用JQ 1（50 mg/kg/天）或媒介物对照（DMSO）共处理。在体外研究中，我们通过qPCR测定MMP基因的mRNA表达，并通过试剂盒和明胶酶谱法测定其活性。BET布罗莫结构域抑制导致腹主动脉直径减小（P < 0.05），通过体内血管超声和离体病理评估测量腹主动脉直径。在追求这种作用于AAA的机制中，我们观察到JQ 1治疗导致体外和体内金属蛋白酶基因表达和酶活性下调。结论：BET布罗莫结构域抑制可改善AAA病理后遗症，这种作用可能是通过抑制MMP基因表达及其活性来实现的。(C)2016爱思唯尔爱尔兰有限公司版权所有。
Background: Excessive degradation of extracellular matrix by matrix metalloproteinases (MMP) is the major pathological feature of abdominal aortic aneurysm (AAA). Suppression of extracellular matrix degradation attenuates AAA initiation and progression in preclinical models. In the present study, we wanted to test the effect of JQ1, a small chemical molecule that selectively targets bromodomain and extra-terminal domain (BET), on AngII induced AAA formation in ApoE(-/-) mice.Methods and results: To study the role of BET bromodomain in AAA pathogenesis, male ApoE-/- mice were infused with angiotensin II (AngII, 1000 ng/kg/min) for 21 days and cotreated with JQ1 (50 mg/kg daily) or vehicle control (DMSO). In the in vitro study, we determined the mRNA expression of MMP genes by qPCR and their activity both by the kit and gelatin zymography assay. BET bromodomain inhibition resulted in decreased abdominal aortic diameter (P < 0.05) measured by in vivo vascular ultrasound and ex vivo pathologic assessment of aortas. In pursuit of mechanisms for this effect on AAA, we observed that JQ1 treatment led to a downregulation of metalloproteinase gene expression and enzymatic activity both in vitro and in vivo. Conclusions: BET bromodomain inhibition improved AAA pathological sequelae, and this effect might be achieved though suppression of MMP genes expression and their activity. (C) 2016 Elsevier Ireland Ltd. All rights reserved.