PDF(Pubmed)
Abstract：
OBJECTIVE: Atrial structural and electrical remodelling is a major reason for the initiation and perpetuation of atrial fibrillation (AF). Ubiquitin-specific protease 38 (USP38) is a deubiquitinating enzyme, but its function in the heart remains unknown. The aim of this study was to investigate the effect of USP38 in pressure overload-induced AF.
RESULTS: Cardiac-specific knockout USP38 and cardiac-specific transgenic USP38 mice and their corresponding control mice were used in this study. After 4 weeks with or without aortic banding (AB) surgery, atrial echocardiography, atrial histology, electrophysiological study, and molecular analysis were assessed. Ubiquitin-specific protease 38 knockout mice showed a remarkable improvement in vulnerability to AF, atrial weight and diameter, atrial fibrosis, and calcium-handling protein expression after AB surgery. Conversely, USP38 overexpression further increased susceptibility to AF by exacerbating atrial structural and electrical remodelling. Mechanistically, USP38 interacted with and deubiquitinated nuclear factor-kappa B (NF-κB), and USP38 overexpression increased the level of p-NF-κB in vivo and in vitro, accompanied by the upregulation of NOD-like receptor protein 3 (NLRP3) and inflammatory cytokines, suggesting that USP38 contributes to adverse effects by driving NF-κB/NLRP3-mediated inflammatory responses.
CONCLUSIONS: Overall, our study indicates that USP38 promotes pressure overload-induced AF through targeting NF-κB/NLRP3-mediated inflammatory responses.
RESULTS: Cardiac-specific knockout USP38 and cardiac-specific transgenic USP38 mice and their corresponding control mice were used in this study. After 4 weeks with or without aortic banding (AB) surgery, atrial echocardiography, atrial histology, electrophysiological study, and molecular analysis were assessed. Ubiquitin-specific protease 38 knockout mice showed a remarkable improvement in vulnerability to AF, atrial weight and diameter, atrial fibrosis, and calcium-handling protein expression after AB surgery. Conversely, USP38 overexpression further increased susceptibility to AF by exacerbating atrial structural and electrical remodelling. Mechanistically, USP38 interacted with and deubiquitinated nuclear factor-kappa B (NF-κB), and USP38 overexpression increased the level of p-NF-κB in vivo and in vitro, accompanied by the upregulation of NOD-like receptor protein 3 (NLRP3) and inflammatory cytokines, suggesting that USP38 contributes to adverse effects by driving NF-κB/NLRP3-mediated inflammatory responses.
CONCLUSIONS: Overall, our study indicates that USP38 promotes pressure overload-induced AF through targeting NF-κB/NLRP3-mediated inflammatory responses.
摘要：
目的：心房结构和电重构是房颤（AF）发生和延续的主要原因。泛素特异性蛋白酶38（USP38）是一种去泛素化酶，但是它在心脏中的功能仍然未知。这项研究的目的是研究USP38在压力过载诱发的AF中的作用。
结果：本研究使用心脏特异性敲除USP38和心脏特异性转基因USP38小鼠及其相应的对照小鼠。在有或没有主动脉束带（AB）手术的4周后，心房超声心动图,心房组织学,电生理学研究,和分子分析进行了评估。泛素特异性蛋白酶38敲除小鼠对AF的易损性显着改善，心房重量和直径，心房纤维化,AB手术后钙处理蛋白的表达。相反，USP38过表达通过加重心房结构和电重塑进一步增加了对AF的易感性。机械上,USP38与去泛素化的核因子-κB（NF-κB）相互作用，USP38过表达增加了体内和体外p-NF-κB的水平，伴随着NOD样受体蛋白3（NLRP3）和炎症细胞因子的上调，提示USP38通过驱动NF-κB/NLRP3介导的炎症反应而导致不良反应。
结论：总体而言，我们的研究表明,USP38通过靶向NF-κB/NLRP3介导的炎症反应促进压力超负荷诱导的房颤.
结果：本研究使用心脏特异性敲除USP38和心脏特异性转基因USP38小鼠及其相应的对照小鼠。在有或没有主动脉束带（AB）手术的4周后，心房超声心动图,心房组织学,电生理学研究,和分子分析进行了评估。泛素特异性蛋白酶38敲除小鼠对AF的易损性显着改善，心房重量和直径，心房纤维化,AB手术后钙处理蛋白的表达。相反，USP38过表达通过加重心房结构和电重塑进一步增加了对AF的易感性。机械上,USP38与去泛素化的核因子-κB（NF-κB）相互作用，USP38过表达增加了体内和体外p-NF-κB的水平，伴随着NOD样受体蛋白3（NLRP3）和炎症细胞因子的上调，提示USP38通过驱动NF-κB/NLRP3介导的炎症反应而导致不良反应。
结论：总体而言，我们的研究表明,USP38通过靶向NF-κB/NLRP3介导的炎症反应促进压力超负荷诱导的房颤.
