Department of Neurological Intensive Care Unit, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China.
Department of Intensive Care Unit, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China.
Exp Cell Res. 2022 Jan 1;410(1):112954. doi: 10.1016/j.yexcr.2021.112954. Epub 2021 Nov 29.
The RING-domain E3 ubiquitin ligase RNF146 is an enzyme that plays an important role in ubiquitin-proteasomal protein degradation and participates in various pathophysiological processes. However, its role in cardiac hypertrophy is unclear. In the present work, thoracic transverse aortic constriction (TAC) was performed in transgenic mice with RNF146 knockout mice (KO) and wild-type mice, and neonatal rat cardiomyocytes (NRCMs) were subjected to angiotensin II (Ang II) stimulation to induce cardiac hypertrophy in vitro and in vivo. RNF146 expression was significantly increased in hypertrophied murine hearts and Ang II-stimulated NRCMs. RNF146-KO mice and knockdown of RNF146 NRCMs attenuated TAC- or Ang II-stimulated cardiac hypertrophy. Conversely, enforced expression of RNF146 aggravated these changes. Mechanistically, we found that RNF146 KO or knockdown increased the activation of the AMP-activated protein kinase (AMPK) pathway. Furthermore, we found that RNF146 KO or knockdown decreased ubiquitination of Liver kinase B1 (LKB1), which promoted the activation of the AMPK pathway in a dependent manner. In conclusion, RNF146 targets LKB1 protein for ubiquitin-proteasome degradation in cardiomyocytes and subsequently promotes cardiac hypertrophy by suppressing the activation of the AMPK signaling pathway.
环指 E3 泛素连接酶 RNF146 是一种在泛素-蛋白酶体蛋白降解中起重要作用的酶，参与各种病理生理过程。然而，其在心肌肥厚中的作用尚不清楚。本研究在 RNF146 敲除（KO）转基因小鼠和野生型小鼠中进行了胸主动脉缩窄（TAC），并在体外和体内用血管紧张素 II（Ang II）刺激新生大鼠心肌细胞（NRCMs）诱导心肌肥厚。在肥厚的鼠心中和 Ang II 刺激的 NRCMs 中，RNF146 的表达显著增加。RNF146-KO 小鼠和 RNF146 NRCMs 的敲低减弱了 TAC 或 Ang II 刺激引起的心肌肥厚。相反，强制表达 RNF146 则加剧了这些变化。机制上，我们发现 RNF146 KO 或敲低增加了 AMP 激活的蛋白激酶（AMPK）通路的激活。此外，我们发现 RNF146 KO 或敲低减少了肝激酶 B1（LKB1）的泛素化，从而依赖于 LKB1 促进了 AMPK 通路的激活。总之，RNF146 将 LKB1 蛋白作为靶标进行泛素蛋白酶体降解，从而通过抑制 AMPK 信号通路的激活促进心肌肥厚。
