LINC01588 regulates WWP2-mediated cardiomyocyte injury by interacting with HNRNPL
LINC01588 regulates WWP2-mediated cardiomyocyte injury by interacting with HNRNPL
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DOI：
10.1002/tox.23512
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发表时间：
2022-03-08
影响因子：
4.5
通讯作者：
Zhang, Yunqing
中科院分区：
文献类型：
--
作者：
Song, Yanbin;Ren, Xiaoyue;Zhang, Yunqing
缺血缺氧引起的心肌细胞功能障碍和细胞凋亡是许多急、慢性心脏病的共同特征。E3泛素连接酶（WWP 2）是一种重要的调节因子，参与了多种疾病的发病机制。虽然最近的一些报道提示了WWP 2在心功能不全中的潜在作用，然而，其确切的作用以及其在缺血缺氧心肌细胞中的表达如何调节仍然是难以捉摸的。在此，我们发现缺氧/复氧（A/R）处理的心肌细胞中，WWP 2蛋白水平以时间依赖性方式诱导，伴随着LINC 01588和HNRNPL的同步表达。LINC 01588的敲低增加了心肌细胞凋亡、氧化应激水平和促炎细胞因子基因的表达，下调了WWP 2的表达，并促进了导致心肌细胞功能障碍的SEPT 4基因的表达，SEPT 4基因是WWP 2的靶基因。LINC 01588过表达改善A/R处理的心肌细胞的功能，上调WWP 2的表达，降低SEPT 4的表达。在机制探讨中，我们发现LINC 01588可以直接与HNRNPL蛋白结合，而HNRNPL蛋白可以与WWP 2相互作用，提示WWP 2参与了A/R处理心肌细胞中LINC 01588的调节。此外，WWP 2抑制降低了LINC 01588在A/R诱导的心肌功能障碍中的保护作用。最后，我们证明了LINC 01588过表达改善了小鼠体内的急性心肌梗死。总之，LINC 01588通过与HNRNPL相互作用并促进WWP 2介导的SEPT 4降解来改善A/R诱导的心肌细胞功能障碍。
Cardiomyocyte dysfunction and apoptosis induced by ischemia-hypoxia are common features of many acute and chronic heart diseases. WW domain-containing E3 ubiquitin ligase (WWP2) has been identified as an important regulator in pathogenesis of some health-threatening diseases. Although a couple of recent reports prompted the potential role of WWP2 in heart dysfunction, however, its exact role and how its expression was regulated in ischemic-hypoxic cardiomyocytes are still elusive. Here, we found that WWP2 protein level was induced in anoxia/reoxygenation (A/R) treated cardiomyocytes in a time-dependent manner, accompanied by synchronous expression of LINC01588 and HNRNPL. Knockdown of LINC01588 increased cardiomyocyte apoptosis, the level of oxidative stress, and expression of pro-inflammatory cytokine genes, down-regulated the expression of WWP2 and promoted expression of SEPT4 gene that contributed to cardiomyocyte dysfunction and was a target gene of WWP2. LINC01588 overexpression improved the functions of A/R treated cardiomyocytes, up-regulated WWP2 and reduced SEPT4 expression. In the mechanism exploration, we found that LINC01588 could directly bind with HNRNPL protein that could interact with WWP2, suggesting that WWP2 was involved in the regulation of LINC01588 in A/R treated cardiomyocytes. Moreover, WWP2 inhibition declined the protective role of LINC01588 in cardiomyocyte dysfunction induced by A/R. Finally, we demonstrated that LINC01588 overexpression improved acute myocardial infarction in mice in vivo. In conclusion, LINC01588 improved A/R-induced cardiomyocyte dysfunction by interacting with HNRNPL and promoting WWP2-mediated degradation of SEPT4.