UCHL1 protects against ischemic heart injury via activating HIF-1α signal pathway.
UCHL1 protects against ischemic heart injury via activating HIF-1α signal pathway.
复制标题
DOI：
10.1016/j.redox.2022.102295
复制
发表时间：
2022-06
期刊：
影响因子：
11.4
通讯作者：
Zhu H
中科院分区：
文献类型：
--
作者：
Geng B;Wang X;Park KH;Lee KE;Kim J;Chen P;Zhou X;Tan T;Yang C;Zou X;Janssen PM;Cao L;Ye L;Wang X;Cai C;Zhu H
泛素羧基末端酯酶L1（UCHL 1）被认为是一种神经元特异性蛋白，通过去泛素化和稳定α-突触核蛋白等关键病理蛋白，在帕金森病和脑卒中中发挥重要作用。在本研究中，我们发现心肌梗死（MI）后小鼠和人心肌细胞中UCHL 1显着增加。当使用LDN-57444（一种UCHL 1的药理学抑制剂）治疗接受MI手术的小鼠时，我们发现与溶媒治疗的心脏相比，给予LDN-57444会损害心脏功能，表明UCHL 1在响应MI时具有潜在的保护作用。当通过CRISPR/Cas 9基因编辑技术在人类诱导多能干细胞（hiPSC）中敲除UCHL 1时，我们发现与野生型心肌细胞相比，来自UCHL 1 −/− hiPSC的心肌细胞更容易受到缺氧/再氧合诱导的损伤。为了研究UCHL 1的潜在靶点，进行了基于BioID的邻近标记方法，然后进行质谱分析。结果提示UCHL 1可与HIF-1α结合并稳定心肌梗死后的HIF-1α。事实上，通过Western印迹法测定，HIF-1α在UCHL 1 −/−细胞中的表达较低，通过真实的时间RT-PCR定量，HIF-1α靶基因在UCHL 1 −/−细胞中也受到抑制。重组UCHL 1（rUCHL 1）蛋白经E.大肠杆菌发酵和腹膜内（I. P.）传递给老鼠。我们发现，与对照组相比，rUCHL 1给药可以显着保护MI后的心脏功能。最后，在新生小鼠中进行腺相关病毒介导的心脏特异性UCHL 1递送（AAV 9-cTNT-m-UCHL 1）。UCHL 1过表达的心脏与对照病毒感染的心脏相比，对MI损伤具有更强的抵抗力。总之，我们的数据揭示了UCHL 1通过稳定HIF-1α和促进HIF-1α信号转导对MI的新的保护作用。
Ubiquitin carboxyl-terminal esterase L1 (UCHL1) has been thought to be a neuron specific protein and shown to play critical roles in Parkinson's Disease and stroke via de-ubiquiting and stabilizing key pathological proteins, such as α-synuclein. In the present study, we found that UCHL1 was significantly increased in both mouse and human cardiomyocytes following myocardial infarction (MI). When LDN-57444, a pharmacological inhibitor of UCHL1, was used to treat mice subjected to MI surgery, we found that administration of LDN-57444 compromised cardiac function when compared with vehicle treated hearts, suggesting a potential protective role of UCHL1 in response to MI. When UCHL1 was knockout by CRISPR/Cas 9 gene editing technique in human induced pluripotent stem cells (hiPSCs), we found that cardiomyocytes derived from UCHL1−/− hiPSCs were more susceptible to hypoxia/re-oxygenation induced injury as compared to wild type cardiomyocytes. To study the potential targets of UCHL1, a BioID based proximity labeling approach followed by mass spectrum analysis was performed. The result suggested that UCHL1 could bind to and stabilize HIF-1α following MI. Indeed, expression of HIF-1α was lower in UCHL1−/− cells as determined by Western blotting and HIF-1α target genes were also suppressed in UCHL1−/− cells as quantified by real time RT-PCR. Recombinant UCHL1 (rUCHL1) protein was purified by E. Coli fermentation and intraperitoneally (I.P.) delivered to mice. We found that administration of rUCHL1 could significantly preserve cardiac function following MI as compared to control group. Finally, adeno associated virus mediated cardiac specific UCHL1 delivery (AAV9-cTNT-m-UCHL1) was performed in neonatal mice. UCHL1 overexpressing hearts were more resistant to MI injury as compare to the hearts infected with control virus. In summary, our data revealed a novel protective role of UCHL1 on MI via stabilizing HIF-1α and promoting HIF-1α signaling.
登录
查看更多内容
影响因子：
1.6
作者：
Dang Ngoc Anh Suong;Dang Thi Phuong Thao;Tran Linh Thuoc
通讯作者：
Tran Linh Thuoc
DOI：
10.1042/bcj20160082
发表时间：
2016-08-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Bishop P;Rocca D;Henley JM
通讯作者：
Henley JM
影响因子：
64.8
作者：
Nakada, Yuji;Canseco, Diana C.;Sadek, Hesham A.
通讯作者：
Sadek, Hesham A.
影响因子：
7.3
作者：
LOWE, J;MCDERMOTT, H;WILKINSON, KD
通讯作者：
WILKINSON, KD
影响因子：
4.6
作者：
Lei, Qian;Yi, Tao;Wang, Yanggan
通讯作者：
Wang, Yanggan