Manipulating PML SUMOylation via Silencing UBC9 and RNF4 Regulates Cardiac Fibrosis

被引：78

作者：

Liu, Yu ^{[1
]}

Zhao, Dan ^{[2
]}

Qiu, Fang ^{[1
]}

Zhang, Ling-Ling ^{[1
]}

Liu, Shang-Kun ^{[1
]}

Li, Yuan-Yuan ^{[1
]}

Liu, Mei-Tong ^{[1
]}

Wu, Di ^{[1
]}

Wang, Jia-Xin ^{[1
]}

Ding, Xiao-Qing ^{[2
]}

Liu, Yan-Xin ^{[1
]}

Dong, Chang-Jiang ^{[1
]}

Shao, Xiao-Qi ^{[1
]}

Yang, Bao-Feng ^{[1
]}

Chu, Wen-Feng ^{[1
]}

机构：

[1] Harbin Med Univ, Dept Pharmacol, Key Lab Cardiovascular Res,Coll Pharm, Minist Educ,State Prov Key Labs Biomed Pharmaceut, Harbin 150081, Heilongjiang, Peoples R China

[2] Harbin Med Univ, Affiliated Hosp 2, Dept Clin Pharm, Key Labs,Educ Minist Myocardial Ischemia Mech & T, Harbin 150081, Heilongjiang, Peoples R China

来源：

MOLECULAR THERAPY | 2017年 / 25卷 / 03期

基金：

中国国家自然科学基金; 中国博士后科学基金;

关键词：

NUCLEAR-BODIES; TRANSCRIPTIONAL ACTIVITY; UBIQUITIN LIGASE; RAR-ALPHA; SUMO; PIN1; DIFFERENTIATION; HYPERTROPHY; CONTRIBUTES; FATE;

D O I：

10.1016/j.ymthe.2016.12.021

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 [微生物学]; 090105 [作物生产系统与生态工程];

摘要：

The promyelocytic leukemia protein (PML) is essential in the assembly of dynamic subnuclear structures called PML nuclear bodies (PML-NBs), which are involved in regulating diverse cellular functions. However, the possibility of PML being involved in cardiac disease has not been examined. In mice undergoing transverse aortic constriction (TAC) and arsenic trioxide (ATO) injection, transforming growth factor beta 1 (TGF-(beta 1) was upregulated along with dynamic alteration of PML SUMOylation. In cultured neonatal mouse cardiac fibroblasts (NMCFs), ATO, angiotensin II (Ang II), and fetal bovine serum (FBS) significantly triggered PML SUMOylation and the assembly of PML-NBs. Inhibition of SUMOylated PML by silencing UBC9, the unique SUMO E2-conjugating enzyme, reduced the development of cardiac fibrosis and partially improved cardiac function in TAC mice. In contrast, enhancing SUMOylated PML accumulation, by silencing RNF4, a poly-SUMO-specific E3 ubiquitin ligase, accelerated the induction of cardiac fibrosis and promoted cardiac function injury. PML colocalized with Pinl (a positive regulator for TGF-(beta 1 mRNA expression in PML-NBs) and increased TGF-beta 1 activity. These findings suggest that the UBC9/PML/RNF4 axis plays a critical role as an important SUMO pathway in cardiac fibrosis. Modulating the protein levels of the pathway provides an attractive therapeutic target for the treatment of cardiac fibrosis and heart failure.

引用

页码：666 / 678

页数：13

共 39 条

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