Administration of ubiquitin-activating enzyme UBA1 inhibitor PYR-41 attenuates angiotensin II-induced cardiac remodeling in mice
Administration of ubiquitin-activating enzyme UBA1 inhibitor PYR-41 attenuates angiotensin II-induced cardiac remodeling in mice
复制标题
给予泛素激活酶 UBA1 抑制剂 PYR-41 可减弱血管紧张素 II 诱导的小鼠心脏重塑。
DOI：
10.1016/j.bbrc.2018.09.100
复制
发表时间：
2018-10-20
影响因子：
3.1
通讯作者：
Li, Hui-Hua
中科院分区：
文献类型：
--
作者：
Shu, Qing;Lai, Song;Li, Hui-Hua
病理性心脏肥大是心脏病的主要危险因素。泛素蛋白酶体系统（UPS）是参与心脏肥厚重塑发展的主要细胞内蛋白质降解系统。泛素激活酶 E1 是 UPS 的关键成分，它催化泛素结合的第一步，以标记细胞蛋白通过蛋白酶体降解。然而，E1 (UBA1) 在调节血管紧张素 II (Ang 11) 输注小鼠肥厚重塑中的功能作用仍不清楚。在这项研究中，雄性野生型小鼠接受 UBA1 抑制剂 PYR-41 5 和 10 mg 两种剂量的治疗，并输注 Ang II (1000 ng/kg/min)，持续 14 天。使用尾套系统检测收缩压。通过超声心动图评估心脏功能。通过组织学检查分析肥大性重塑。通过实时定量PCR和免疫印迹分析检测基因和蛋白的表达。 14 天后，Ang II 输注显着增加了心脏中 mRNA 和蛋白质水平的 UBA1 表达。此外，与生理盐水处理的对照组相比，Ang II输注的小鼠表现出收缩压、代偿性心脏功能、肥厚、间质纤维化、炎症和氧化应激显着增加，而这些作用在PYR-41处理的小鼠中呈剂量依赖性减弱。这些有益作用主要与抑制 PTEN 降解和多种下游介质（AKT、ERK1/2、STAT3、TGF-beta/Smad2/3 和 NF-kappa B(p65)）有关。总之，这些结果表明抑制 UBAI 可以抑制 Ang II 诱导的肥厚性重塑，并表明给予低剂量 PYR-41 可能是治疗高血压心脏病的新的潜在治疗方法。 (C) 2018 Elsevier Inc. 保留所有权利。
Pathological cardiac hypertrophy is the main risk factor for heart diseases. The ubiquitin-proteasome system (UPS) is the major intracellular protein degradation system involved in the development of cardiac hypertrophic remodeling. Ubiquitin-activating enzyme E1, a key component of the UPS, catalyzes the first step in ubiquitin conjugation to mark cellular proteins for degradation via proteasome. However, the functional role of E1 (UBA1) in regulation of hypertrophic remodeling in angiotensin II (Ang 11)-infused mice remains unknown. In this study, male wild-type mice were treated with UBA1 inhibitor PYR-41 at two doses of 5 and 10 mg and infused with Ang II (1000 ng/kg/min) for 14 days. Systolic blood pressure was detected by using tail-cuff system. Cardiac function was assessed by echocardiography. Hypertrophic remodeling was analyzed examined by histological examinations. The expressions of genes and proteins were detected by quantitative real-time PCR and immunoblotting analysis. After 14 days, Ang II infusion significantly increased UBA1 expression at both mRNA and protein levels in the hearts. Furthermore, Ang II-infused mice showed a significant increase in systolic blood pressure compensatory cardiac function, hypertrophy, interstitial fibrosis, inflammation and oxidative stress compared with saline-treated controls, whereas these effects were dose-dependently attenuated in PYR-41-treated mice. These beneficial actions were associated mainly with inhibition of PTEN degradation and multiple downstream mediators (AKT, ERK1/2, STAT3, TGF-beta/Smad2/3 and NF-kappa B(p65)). In conclusion, these results indicate that inhibition of UBAI suppresses Ang II-induced hypertrophic remodeling, and suggest that administration of low dose PYR-41 may be a new potential therapeutic approach for treating hypertensive heart diseases. (C) 2018 Elsevier Inc. All rights reserved.