Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China.
Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Shanghai, 200092, China.
Arch Biochem Biophys. 2022 Jul 30;724:109266. doi: 10.1016/j.abb.2022.109266. Epub 2022 May 3.
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.
纤维化是心肌梗死后心脏功能障碍的关键原因之一。了解导致纤维化的潜在分子机制对于开发有效的治疗方法至关重要。最近，含有 OUT 结构域的 7B 型（OTUD7B），也称为 Cezanne，作为一种多功能去泛素酶，已被发现可在癌症和血管疾病中发挥多种作用，并控制许多重要的信号通路，包括炎症、增殖等。然而，OTUD7B 是否在 MI 引起的纤维化中发挥作用尚不清楚。我们的研究旨在探讨 OTUD7B 在心肌纤维化中的作用，并研究其潜在机制。我们发现，OTUD7B 在 MI 大鼠模型和低氧条件下以及 TGF-β1 处理后的培养心肌成纤维细胞（CFs）中的表达下调。在体外，使用小干扰 RNA（siRNA）沉默 OTUD7B 会增加 CFs 中 α-SMA（平滑肌肌动蛋白α）和胶原 Ⅰ的水平，而使用腺病毒过表达 OTUD7B 则会降低其表达。在机制上，OTUD7B 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，而 ERK/P38 MAPK 参与了这一调节过程。在体外，过表达 OTUD7B 下调 FAK 的磷酸化水平，从而抑制 ERK/P38 的磷酸化，导致 α-SMA 和胶原 Ⅰ表达减少，而 OTUD7B 敲低则显示出相反的结果。这些发现表明，OTUD7B 可能成为 MI 后纤维化的一种潜在有效治疗策略。
