Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, SC 29208, USA.
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, SC 29208, USA.
J Mol Cell Cardiol. 2015 Jul;84:143-53. doi: 10.1016/j.yjmcc.2015.04.012. Epub 2015 Apr 30.
Ubiquitin proteasome system (UPS) consists of ubiquitin, ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), proteasomes, and deubiquitinating enzymes (DUBs). Ubiquitin, E1s, several E2s, E3s, and proteasomes play an important role in the regulation of cardiac homeostasis and dysfunction; however, less is known about the role of DUBs in the heart. Here, we uncovered a crucial role of cyclindromatosis (CYLD), a DUB, in mediating cardiac maladaptive remodeling and dysfunction. CYLD expression was dramatically upregulated in the cardiomyocytes of hypertrophic and failing human and murine hearts. Knockout of CYLD improved survival rate and alleviated cardiac hypertrophy, fibrosis, apoptosis, oxidative stress, and dysfunction in mice that were subjected to sustained pressure overload induced by transverse aortic constriction. Deep sequencing and gene array analyses revealed that the most dramatically changed genes are those involving in the free radical scavenging pathway and cardiovascular disease, including fos, jun, myc, and nuclear factor erythroid-2 related factor 2 (Nrf2) in the heart. Moreover, knockdown of CYLD enhanced mitogen-activated protein kinase (MAPK) ERK- and p38-mediated expression of c-jun, c-fos, and c-myc, which govern Nrf2 expression in cardiomyocytes. The CYLD deficiency-induced suppression of reactive oxygen species (ROS) formation, death and hypertrophy in cardiomyocytes was blocked by additional knockdown of Nrf2. Taken together, our findings demonstrate for the first time that CYLD mediates cardiac maladaptive remodeling and dysfunction, most likely via enhancing myocardial oxidative stress in response to pressure overload. At the molecular level, CYLD interrupts the ERK- and p38-/AP-1 and c-Myc pathways to suppress Nrf2-operated antioxidative capacity, thereby enhancing oxidative stress in the heart.
泛素蛋白酶体系统（UPS）由泛素、泛素激活酶（E1s）、泛素结合酶（E2s）、泛素连接酶（E3s）、蛋白酶体和去泛素化酶（DUBs）组成。泛素、E1s、几种 E2s、E3s 和蛋白酶体在心脏内稳态和功能障碍的调节中起着重要作用；然而，关于 DUBs 在心脏中的作用知之甚少。在这里，我们揭示了一种去泛素化酶 CYLD 在介导心脏适应性重构和功能障碍中的关键作用。CYLD 的表达在肥厚和衰竭的人类和鼠心脏的心肌细胞中显著上调。在接受持续的主动脉缩窄引起的压力超负荷的小鼠中，CYLD 的缺失可提高存活率并减轻心脏肥大、纤维化、细胞凋亡、氧化应激和功能障碍。深度测序和基因芯片分析显示，变化最显著的基因是那些涉及自由基清除途径和心血管疾病的基因，包括 fos、jun、myc 和核因子红细胞 2 相关因子 2（Nrf2）。此外，CYLD 的敲低增强了丝裂原激活蛋白激酶（MAPK）ERK 和 p38 介导的 c-jun、c-fos 和 c-myc 的表达，这控制了心肌细胞中 Nrf2 的表达。在心肌细胞中，CYLD 缺失诱导的活性氧（ROS）形成、死亡和肥大的抑制作用被 Nrf2 的额外敲低所阻断。总之，我们的研究结果首次表明，CYLD 介导心脏适应性重构和功能障碍，很可能是通过增强心肌对压力超负荷的氧化应激反应。在分子水平上，CYLD 打断了 ERK 和 p38/AP-1 和 c-Myc 途径，抑制了 Nrf2 操作的抗氧化能力，从而增强了心脏的氧化应激。
