Knockdown of endogenous RNF4 exacerbates ischaemia-induced cardiomyocyte apoptosis in mice.
Knockdown of endogenous RNF4 exacerbates ischaemia-induced cardiomyocyte apoptosis in mice.
复制标题
内源性 RNF4 的敲低加剧了小鼠缺血诱导的心肌细胞凋亡
DOI：
10.1111/jcmm.15363
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发表时间：
2020-09
影响因子：
5.3
通讯作者：
Chu W
中科院分区：
文献类型：
--
作者：
Qiu F;Han Y;Shao X;Paulo P;Li W;Zhu M;Tang N;Guo S;Chen Y;Wu H;Zhao D;Liu Y;Chu W
RNF4是一种多相扑特异性E3泛素连接酶，与蛋白质降解、DNA损伤修复和肿瘤进展有关。然而，RNF4对心肌细胞的作用仍有待进一步研究。在这里，我们确定了RNF4在缺血心脏和氧化应激诱导的心肌细胞凋亡中的变化。在心肌梗死(MI)或H_2O_2/ATO治疗后，RNF4迅速升高，然后逐渐降低。PML SUMO化和PML核体(PML-NB)的形成在氧化应激条件下先增强后降解。活性氧(ROS)抑制剂能抑制RNF4表达的上调和PML SUMO化。PML过表达和小干扰RNA(SiRNA)敲除RNF4可促进PML SUMO化，促进P53募集和激活，加剧过氧化氢/ATO诱导的心肌细胞凋亡，这种作用可被P53抑制部分逆转。在体内，通过体内腺相关病毒感染下调内源性RNF4，恶化了MI后的结构重建，包括更广泛的间质纤维化和严重的结构断裂和无序。此外，RNF4基因敲除加重了心肌梗死模型缺血诱导的心功能障碍。我们的结果揭示了一个由RNF4、PML和P53组成的新的心肌细胞凋亡调控模型。这些蛋白的调节可能为治疗心脏缺血提供一种新的方法。
RNF4, a poly‐SUMO‐specific E3 ubiquitin ligase, is associated with protein degradation, DNA damage repair and tumour progression. However, the effect of RNF4 in cardiomyocytes remains to be explored. Here, we identified the alteration of RNF4 from ischaemic hearts and oxidative stress‐induced apoptotic cardiomyocytes. Upon myocardial infarction (MI) or H2O2/ATO treatment, RNF4 increased rapidly and then decreased gradually. PML SUMOylation and PML nuclear body (PML‐NB) formation first enhanced and then degraded upon oxidative stress. Reactive oxygen species (ROS) inhibitor was able to attenuate the elevation of RNF4 expression and PML SUMOylation. PML overexpression and RNF4 knockdown by small interfering RNA (siRNA) enhanced PML SUMOylation, promoted p53 recruitment and activation and exacerbated H2O2/ATO‐induced cardiomyocyte apoptosis which could be partially reversed by knockdown of p53. In vivo, knockdown of endogenous RNF4 via in vivo adeno‐associated virus infection deteriorated post‐MI structure remodelling including more extensive interstitial fibrosis and severely fractured and disordered structure. Furthermore, knockdown of RNF4 worsened ischaemia‐induced cardiac dysfunction of MI models. Our results reveal a novel myocardial apoptosis regulation model that is composed of RNF4, PML and p53. The modulation of these proteins may provide a new approach to tackling cardiac ischaemia.
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影响因子：
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作者：
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