Tripartite Motif 8 Contributes to Pathological Cardiac Hypertrophy Through Enhancing Transforming Growth Factor β-Activated Kinase 1-Dependent Signaling Pathways
Tripartite Motif 8 Contributes to Pathological Cardiac Hypertrophy Through Enhancing Transforming Growth Factor β-Activated Kinase 1-Dependent Signaling Pathways
复制标题
三联基序 8 通过增强转化生长因子 β 激活激酶 1 依赖性信号通路导致病理性心脏肥大
DOI：
10.1161/hypertensionaha.116.07741
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发表时间：
2017-02-01
期刊：
影响因子：
8.3
通讯作者：
Li, Hongliang
中科院分区：
文献类型：
--
作者：
Chen, Lijuan;Huang, Jia;Li, Hongliang
三分基序（TRIM）8作为E3泛素连接酶，与多种底物相互作用并泛素化，并参与各种病理过程。然而，TRIM 8在心脏中的功能在很大程度上仍然没有表征。本研究旨在探讨TRIM 8在病理性心肌肥厚发生发展中的作用。在几个实验中检查过表达或缺乏TRIM 8的小鼠和分离的新生大鼠心肌细胞。通过超声心动图、病理学和分子生物学分析，分析主动脉缩窄引起的心肌肥厚的影响。我们的研究结果表明，心脏中TRIM 8过表达加剧了由主动脉缩窄引发的心脏肥大。相比之下，病理性心脏肥大的发展在TRIM 8缺陷的心脏中被深度阻断。从机制上讲，我们的研究表明TRIM 8可能通过促进转化生长因子β激活激酶1（TAK 1）-p38/JNK信号通路的激活而引起心脏损害。在血管紧张素II处理的培养的新生大鼠心肌细胞中观察到类似的结果。使用TAK 1特异性抑制剂5 z-7-ox的拯救实验证实了在TRIM 8介导的病理性心脏肥大中需要TAK 1活化。此外，TRIM 8通过结合并促进TAK 1泛素化而促进TAK 1活化。总之，我们的研究表明，TRIM 8通过加速TAK 1依赖性信号通路的激活在压力超负荷诱导的心脏肥大中起着有害的作用。在线补充资料
Tripartite motif (TRIM) 8 functions as an E3 ubiquitin ligase, interacting with and ubiquitinating diverse substrates, and is implicated in various pathological processes. However, the function of TRIM8 in the heart remains largely uncharacterized. This study aims to explore the role of TRIM8 in the development of pathological cardiac hypertrophy. Mice and isolated neonatal rat cardiomyocytes overexpressing or lacking TRIM8 were examined in several experiments. The effect of aortic banding-induced cardiac hypertrophy was analyzed by echocardiographic, pathological and molecular analyses. Our results indicated that the TRIM8 overexpression in hearts exacerbated the cardiac hypertrophy triggered by aortic banding. In contrast, the development of pathological cardiac hypertrophy was profoundly blocked in TRIM8-deficient hearts. Mechanistically, our study suggests that TRIM8 may elicit cardiodetrimental effects by promoting the activation of transforming growth factor beta-activated kinase 1 (TAK1)-p38/JNK signaling pathways. Similar results were observed in cultured neonatal rat cardiomyocytes treated with angiotensin II. The rescue experiments using the TAK1-specific inhibitor 5z-7-ox confirmed the requirement of TAK1 activation in TRIM8-mediated pathological cardiac hypertrophy. Furthermore, TRIM8 contributed to TAK1 activation by binding to and promoting TAK1 ubiquitination. In conclusion, our study demonstrates that TRIM8 plays a deleterious role in pressure overload-induced cardiac hypertrophy by accelerating the activation of TAK1-dependent signaling pathways. Online Data Supplement