Nuclear Tkt promotes ischemic heart failure via the cleaved Parp1/Aif axis
Nuclear Tkt promotes ischemic heart failure via the cleaved Parp1/Aif axis
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DOI：
10.1007/s00395-022-00925-8
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发表时间：
2022-12-01
影响因子：
9.5
通讯作者：
Jin, Wei
中科院分区：
文献类型：
--
作者：
Wang, Zhiyan;Qiu, Zeping;Jin, Wei
转酮醇酶（Transketolase，Tkt）是磷酸戊糖途径中的一种酶，在肿瘤的发生发展中起着重要的作用。然而，心肌缺血损伤后TKT的作用仍有待阐明。无标记蛋白质组学研究显示，心肌梗死（MI）后小鼠心脏Tkt显著升高。慢病毒介导的Tkt基因敲低可改善心肌缺血损伤后的心肌细胞凋亡并保护心肌收缩功能。相反，Tkt过表达导致相反的效果。诱导条件性心肌细胞Tkt基因敲除小鼠，心肌细胞表达的Tkt被发现在这些模型小鼠的缺血性心力衰竭中发挥内在作用。此外，通过荧光素酶分析和染色质免疫沉淀，Tkt被证明是转录因子Kruppel样因子5（Klf 5）的直接靶点。在心肌细胞在缺血应激，TKT重新分布到核。通过与全长聚（ADP-核糖）聚合酶1（Parp 1）结合，促进其裂解，并随后激活凋亡诱导因子（Aif），核Tkt显示其非代谢功能。总体而言，我们的研究证实，核Tkt升高通过裂解的Parp 1/Aif通路在促进心肌细胞凋亡中发挥非经典作用，导致心功能不全的恶化。
Transketolase (Tkt), an enzyme in pentose phosphate pathway, has been reported to regulate genome instability and cell survival in cancers. Yet, the role of Tkt after myocardial ischemic injury remains to be elucidated. Label-free proteomics revealed dramatic elevation of Tkt in murine hearts after myocardial infarction (MI). Lentivirus-mediated Tkt knockdown ameliorated cardiomyocyte apoptosis and preserved the systolic function after myocardial ischemic injury. In contrast, Tkt overexpression led to the opposite effects. Inducible conditional cardiomyocyte Tkt-knockout mice were generated, and cardiomyocyte-expressed Tkt was found to play an intrinsic role in the ischemic heart failure of these model mice. Furthermore, through luciferase assay and chromatin immunoprecipitation, Tkt was shown to be a direct target of transcription factor Kruppel-like factor 5 (Klf5). In cardiomyocytes under ischemic stress, Tkt redistributed into the nucleus. By binding with the full-length poly(ADP-ribose) polymerase 1 (Parp1), facilitating its cleavage, and activating apoptosis inducible factor (Aif) subsequently, nuclear Tkt demonstrated its non-metabolic functions. Overall, our study confirmed that elevated nuclear Tkt plays a noncanonical role in promoting cardiomyocyte apoptosis via the cleaved Parp1/Aif pathway, leading to the deterioration of cardiac dysfunction.