Yuan Lin, Bu Shichen, Du Meng, Wang Yilong, Ju Chenhui, Huang Dandan, Xu Wenjing, Tan Xin, Liang Minglu, Deng Shan, Yang Liu, Huang Kai
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, Hubei, China.
Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China.
Cardiovasc Res. 2023 Mar 17;119(1):183-194. doi: 10.1093/cvr/cvac039.
The heart undergoes pathological remodelling, featured by the hypertrophic growth of cardiomyocytes and increased cardiac fibrosis, under biomechanical stress such as haemodynamic overload. Ring Finger Protein 207 (RNF207) is an E3 ubiquitin ligase that is predominantly expressed in the heart, but its function remains elusive. In this study, we aimed to explore the role of RNF207 in the development of pathological cardiac hypertrophy and dysfunction.
Transverse aortic constriction (TAC) surgery was performed on mice to induce cardiac hypertrophy. Cardiac function and remodelling were evaluated by echocardiography, histological assessment, and molecular analyses. Our data indicated that RNF207 overexpression (OE) exacerbated cardiac hypertrophy, fibrosis, and systolic dysfunction. In contrast, TAC-induced cardiac remodelling was profoundly blunted in RNF207 knockdown (KD) hearts. In line with the in vivo findings, RNF207 OE augmented, whereas RNF207 KD alleviated, phenylephrine-induced cardiomyocyte hypertrophy in vitro. Mechanistically, we demonstrated that RNF207 elicited detrimental effects by promoting K63-linked ubiquitination of TAK1-binding protein 1 (TAB1), which triggered the autophosphorylation of transforming growth factor-β activated kinase 1 (TAK1) and the activation of downstream p38 and c-Jun N-terminal kinase (JNK)1/2 signalling pathways. In the TAB1-KD cardiomyocytes, RNF207-OE-induced cell hypertrophy was significantly attenuated, indicating that RNF207-induced hypertrophy is, at least in part, TAB1-dependent.
This study demonstrates that RNF207 exacerbates pressure overload-induced cardiac hypertrophy and dysfunction via post-translational modification of TAB1.
在诸如血流动力学过载等生物力学应激下，心脏会经历病理性重塑，其特征为心肌细胞肥大性生长和心脏纤维化增加。环指蛋白207（RNF207）是一种E3泛素连接酶，主要在心脏中表达，但其功能仍不清楚。在本研究中，我们旨在探讨RNF207在病理性心脏肥大和功能障碍发展中的作用。
对小鼠进行横向主动脉缩窄（TAC）手术以诱导心脏肥大。通过超声心动图、组织学评估和分子分析来评估心脏功能和重塑。我们的数据表明，RNF207过表达（OE）加剧了心脏肥大、纤维化和收缩功能障碍。相比之下，在RNF207基因敲低（KD）的心脏中，TAC诱导的心脏重塑明显减弱。与体内研究结果一致，RNF207过表达增强了苯肾上腺素诱导的体外心肌细胞肥大，而RNF207基因敲低则减轻了这种肥大。机制上，我们证明RNF207通过促进TAK1结合蛋白1（TAB1）的K63连接的泛素化发挥有害作用，这触发了转化生长因子-β激活激酶1（TAK1）的自磷酸化以及下游p38和c-Jun氨基末端激酶（JNK）1/2信号通路的激活。在TAB1基因敲低的心肌细胞中，RNF207过表达诱导的细胞肥大明显减弱，表明RNF207诱导的肥大至少部分依赖于TAB1。
本研究表明，RNF207通过对TAB1的翻译后修饰加剧压力超负荷诱导的心脏肥大和功能障碍。
