Zeng Linqi, Zhang Xiaokai, Huang Zihang, Song Shuai, Li Mohan, Wang Tongyao, Sun Aijun, Ge Junbo
Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China.
Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
J Adv Res. 2024 Dec 7. doi: 10.1016/j.jare.2024.12.006.
Cardiac fibrosis, including reactive fibrosis and replacement fibrosis, is a common pathological process in most cardiovascular diseases. The ubiquitin proteasome system (UPS) plays an important role in the development of fibrosis by mediating the degradation and synthesis of proteins involved in transforming growth factor-β (TGF-β)-dependent and TGF-β-independent fibrous pathways.
This review aims to provide an overview of ubiquitinated and deubiquitinated molecules that participating in cardiac fibrosis, with the ultimate purpose to identify promising targets for therapeutic strategies.
The UPS primarily impacts cardiac fibrosis through modulation of the TGF-β signaling pathway targeting key molecules involved, including the TGF-β receptors, Smad2/3/4 complexes, and inhibitory Smad7, thereby influencing fibrotic processes. In addition to its effect on TGF-β signaling, UPS also regulates pro-fibrotic pathways independent of TGF-β, including p53, AKT1-p38, and JNK1/2. Understanding these pathways is critical due to their involvement in diverse fibrotic mechanisms. The interplay between ubiquitination and deubiquitination of crucial pathways and molecules is pivotal in cardiac fibrosis and represents a promising area for identifying novel therapeutic targets. Different types of cardiac fibrosis involve distinct fibrotic pathways, leading to differential effects of ubiquitin ligases (E3 ligases) and deubiquitinating enzymes (DUBs) across various cardiac fibrotic diseases. Insights into UPS-mediated regulation of cardiac fibrosis provide potential anti-fibrotic therapeutic strategies, emphasizing the importance of targeting UPS components specific to the heart for effective therapy against cardiac fibrosis.
心脏纤维化，包括反应性纤维化和替代性纤维化，是大多数心血管疾病中常见的病理过程。泛素蛋白酶体系统（UPS）通过介导参与转化生长因子-β（TGF-β）依赖性和TGF-β非依赖性纤维化途径的蛋白质的降解和合成，在纤维化的发展中起重要作用。
本综述旨在概述参与心脏纤维化的泛素化和去泛素化分子，最终目的是确定有前景的治疗策略靶点。
UPS主要通过调节TGF-β信号通路来影响心脏纤维化，该信号通路靶向参与其中的关键分子，包括TGF-β受体、Smad2/3/4复合物和抑制性Smad7，从而影响纤维化过程。除了对TGF-β信号的影响外，UPS还调节独立于TGF-β的促纤维化途径，包括p53、AKT1-p38和JNK1/2。由于这些途径参与多种纤维化机制，了解它们至关重要。关键途径和分子的泛素化和去泛素化之间的相互作用在心脏纤维化中至关重要，并且是识别新型治疗靶点的一个有前景的领域。不同类型的心脏纤维化涉及不同的纤维化途径，导致泛素连接酶（E3连接酶）和去泛素化酶（DUBs）在各种心脏纤维化疾病中的作用不同。对UPS介导的心脏纤维化调节的深入了解提供了潜在的抗纤维化治疗策略，强调了针对心脏特异性UPS成分进行有效治疗心脏纤维化的重要性。
