OTUD7B (Cezanne) ameliorates fibrosis after myocardial infarction via FAK-ERK/P38 MAPK signaling pathway.
OTUD7B (Cezanne) ameliorates fibrosis after myocardial infarction via FAK-ERK/P38 MAPK signaling pathway.
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DOI：
10.1016/j.abb.2022.109266
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发表时间：
2022-05
影响因子：
3.9
通讯作者：
Jiayan Zhang;Yafang Zha;Y. Jiao;Yanyan Li;Jian Wang;Song Zhang
中科院分区：
文献类型：
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作者：
Jiayan Zhang;Yafang Zha;Y. Jiao;Yanyan Li;Jian Wang;Song Zhang
心肌纤维化是心肌梗死后心功能不全的重要原因之一。了解导致纤维化的潜在分子机制对于开发有效的治疗至关重要。近年来，OUT结构域7 B（OTUD 7 B）又称Cezanne，是一种多功能去泛素化蛋白，在肿瘤和血管疾病中发挥多种作用，控制炎症、增殖等重要信号通路，但OTUD 7 B是否在心肌梗死引起的纤维化中发挥作用尚不清楚。本研究旨在探讨OTUD 7 B在心肌纤维化中的作用及其机制。我们发现，在缺氧条件下和TGF-β1处理后，MI大鼠模型和培养的心脏成纤维细胞（CFs）中OTUD 7 B的表达下调。在体外，使用小干扰RNA（siRNA）沉默OTUD 7 B增加CF中的α-SMA（平滑肌肌动蛋白α）和胶原Ⅰ水平，而使用腺病毒过表达OTUD 7 B降低其表达。在机制上，OTUD 7 B可以调节粘着斑激酶（FAK）的磷酸化，FAK是一种非受体酪氨酸激酶，已被证明是纤维化的潜在介质，ERK/P38 MAPK参与了这一调节过程。在体外，过表达OTUD 7 B可下调FAK的磷酸化水平，进而抑制ERK/P38的磷酸化，从而导致α-SMA和Ⅰ型胶原的表达下降，而敲低OTUD 7 B则表现出相反的结果。这些发现表明OTUD 7 B可能成为MI后抗纤维化的潜在有效治疗策略。
Fibrosis is one of the crucial reasons for cardiac dysfunction after myocardial infarction (MI). Understanding the underlying molecular mechanism that causes fibrosis is crucial to developing effective therapy. Recently, OUT domain-containing 7B (OTUD7B), also called Cezanne, a multifunctional deubiquitylate, has been found to play various roles in cancer and vascular diseases and control many important signaling pathways, including inflammation, proliferation, and so on. However, whether OTUD7B plays a role in fibrosis caused by MI remains unclear. Our study aimed to explore the function of OTUD7B in cardiac fibrosis and investigate the underlying mechanism. We found that the expression of OTUD7B was downregulated in the MI rat model and cultured cardiac fibroblasts (CFs) in hypoxic conditions and after TGF-β1 treatment. In vitro, silencing OTUD7B using small interfering RNA (siRNA) increased α-SMA (smooth muscle actin α) and collagen Ⅰ levels in CFs, whereas the overexpression of OTUD7B using adenovirus decreased their expression. Mechanistically, OTUD7B could regulate the phosphorylation of focal adhesion kinase (FAK), a non-receptor tyrosine kinase that has been proved to act as a potential mediator of fibrosis, and ERK/P38 MAPK was involved in this regulation process. In vitro, overexpression of OTUD7B downregulated the phosphorylation level of FAK and then inhibited ERK/P38 phosphorylation, thus leading to decreased α-SMA and collagen Ⅰ expressions, while OTUD7B knockdown showed an opposite result. These findings suggest that OTUD7B could become a potentially effective therapeutic strategy against fibrosis after MI.