Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, Zhejiang, China.
Department of Cardiology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China.
Biochim Biophys Acta Mol Basis Dis. 2023 Dec;1869(8):166813. doi: 10.1016/j.bbadis.2023.166813. Epub 2023 Jul 23.
Ubiquitin-specific protease 22 (USP22) is a member of the ubiquitin specific protease family (ubiquitin-specific protease, USPs), the largest subfamily of deubiquitinating enzymes, and plays an important role in the treatment of tumors. USP22 is also expressed in the heart. However, the role of USP22 in heart disease remains unclear. In this study, we found that USP22 was elevated in hypertrophic mouse hearts and in angiotensin II (Ang II)-induced cardiomyocytes. The inhibition of USP22 expression with adenovirus significantly rescued hypertrophic phenotype and cardiac dysfunction induced by pressure overloaded. Consistent with in vivo study, silencing by USP22 shRNA expression in vitro had similar results. Molecular analysis revealed that transforming growth factor-β-activating protein 1 (TAK1)-(JNK1/2)/P38 signaling pathway and HIF-1α was activated in the Ang II-induced hypertrophic cardiomyocytes, whereas HIF-1α expression was decreased after the inhibition of USP22. Inhibition of HIF-1α expression reduces TAK1 expression. Co-immunoprecipitation and ubiquitination studies revealed the regulatory mechanism between USP22 and HIF1α.Under hypertrophic stress conditions, USP22 enhances the stability of HIF-1α through its deubiquitination activity, which further activates the TAK1-(JNK1/2)/P38 signaling pathway to lead to cardiac hypertrophy. Inhibition of HIF-1α expression further potentiates the in vivo pathological effects caused by USP22 deficiency. In summary, this study suggests that USP22, through HIF-1α-TAK1-(JNK1/2)/P38 signaling pathway, may be potential targets for inhibiting pathological cardiac hypertrophy induced by pressure overload.
泛素特异性蛋白酶 22（USP22）是泛素特异性蛋白酶家族（泛素特异性蛋白酶，USPs）的成员，是去泛素化酶的最大亚家族，在肿瘤治疗中发挥重要作用。USP22 也在心脏中表达。然而，USP22 在心脏病中的作用尚不清楚。在这项研究中，我们发现 USP22 在肥大的小鼠心脏和血管紧张素 II（Ang II）诱导的心肌细胞中升高。用腺病毒抑制 USP22 表达可显著挽救由压力超负荷引起的肥大表型和心脏功能障碍。与体内研究一致，体外沉默 USP22 shRNA 表达也有类似的结果。分子分析表明，转化生长因子-β激活蛋白 1（TAK1）-（JNK1/2）/P38 信号通路和 HIF-1α在 Ang II 诱导的心肌肥厚细胞中被激活，而在抑制 USP22 后 HIF-1α 的表达减少。抑制 HIF-1α 的表达降低了 TAK1 的表达。免疫共沉淀和泛素化研究揭示了 USP22 和 HIF1α 之间的调节机制。在肥大应激条件下，USP22 通过其去泛素化活性增强 HIF-1α 的稳定性，进一步激活 TAK1-（JNK1/2）/P38 信号通路，导致心脏肥大。抑制 HIF-1α 的表达进一步增强了 USP22 缺乏引起的体内病理效应。总之，这项研究表明，USP22 通过 HIF-1α-TAK1-（JNK1/2）/P38 信号通路，可能是抑制压力超负荷引起的病理性心肌肥大的潜在靶点。
