Inhibition of UCHL1 by LDN-57444 attenuates Ang II-Induced atrial fibrillation in mice.
Inhibition of UCHL1 by LDN-57444 attenuates Ang II-Induced atrial fibrillation in mice.
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LDN-57444 抑制 UCHL1 可减轻 Ang II 诱导的小鼠心房颤动
DOI：
10.1038/s41440-019-0354-z
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发表时间：
2020-03
期刊：
影响因子：
--
通讯作者：
Li HH
中科院分区：
文献类型：
--
作者：
Bi HL;Zhang YL;Yang J;Shu Q;Yang XL;Yan X;Chen C;Li Z;Li HH
心房颤动（AF）是临床实践中最常见的人类心律失常，并且可能由心房炎症和纤维化促进。泛素化是一种重要的翻译后修饰过程，可被去泛素化酶（DUBs）逆转。DUB在调节底物的降解、活性、运输和回收中起关键作用。然而，较少的研究集中在AF的DUBs的作用。在这里，我们研究了泛素C-末端水解酶1（UCHL 1），一个重要的DUB，对血管紧张素II（Ang II）诱导的AF的发展的影响。雄性野生型小鼠用UCHL 1抑制剂LDN 57444（LDN）以40 μg/kg的剂量处理，并输注Ang II（2000 ng/kg/min）3周。我们的研究结果表明，血管紧张素II输注野生型（WT）小鼠有较高的收缩压和增加的发病率和持续时间的AF。相反，这种影响在LDN治疗的小鼠减弱。此外，LDN的管理显着减少血管紧张素II诱导的左心房扩张，纤维化，炎症细胞浸润，和活性氧（ROS）的生产。从机制上讲，与溶剂处理的对照小鼠相比，LDN处理抑制了心房组织中多种信号通路（AKT、ERK 1/2、HIF-1α和TGF-β/smad 2/3通路）的激活和CX 43蛋白的表达。总体而言，我们的研究确定UCHL 1作为一种新的调节剂，有助于血管紧张素II诱导的AF，并表明LDN的管理可能代表一种潜在的治疗方法，用于治疗高血压AF。
Atrial fibrillation (AF) is the most common human arrhythmia in clinical practice and may be promoted by atrial inflammation and fibrosis. Ubiquitination is an important posttranslational modification process that is reversed by deubiquitinating enzymes (DUBs). DUBs play critical roles in modulating the degradation, activity, trafficking, and recycling of substrates. However, less research has focused on the role of DUBs in AF. Here, we investigated the effect of ubiquitin C-terminal hydrolase 1 (UCHL1), an important DUB, on the development of AF induced by angiotensin II (Ang II). Male wild-type mice were treated with the UCHL1 inhibitor LDN57444 (LDN) at a dose of 40 μg/kg and infused with Ang II (2000 ng/kg/min) for 3 weeks. Our results showed that Ang II-infused wild-type (WT) mice had higher systolic blood pressure and an increased incidence and duration of AF. Conversely, this effect was attenuated in LDN-treated mice. Moreover, the administration of LDN significantly reduced Ang II-induced left atrial dilation, fibrosis, inflammatory cell infiltration, and reactive oxygen species (ROS) production. Mechanistically, LDN treatment inhibited the activation of multiple signaling pathways (the AKT, ERK1/2, HIF-1α, and TGF-β/smad2/3 pathways) and the expression of CX43 protein in atrial tissues compared with that in vehicle-treated control mice. Overall, our study identified UCHL1 as a novel regulator that contributes to Ang II-induced AF and suggests that the administration of LDN may represent a potential therapeutic approach for treating hypertensive AF.
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影响因子：
2
作者：
Korantzopoulos P;Letsas KP;Tse G;Fragakis N;Goudis CA;Liu T
通讯作者：
Liu T
影响因子：
4.9
作者：
Tsai, Chia-Ti;Lai, Ling-Ping;Lin, Jiunn-Lee
通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
Li, L
DOI：
10.1152/ajpheart.00771.2012
发表时间：
2013-08-01
影响因子：
4.8
作者：
Rajagopalan, Viswanathan;Zhao, Mingming;Bernstein, Daniel
通讯作者：
Bernstein, Daniel
影响因子：
64.5
作者：
Liu, YC;Fallon, L;Lansbury, PT
通讯作者：
Lansbury, PT