title: Manipulating PML SUMOylation via Silencing UBC9 and RNF4 Regulates Cardiac Fibrosis.
abstract: 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 β1 (TGF-β1) 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 Pin1 (a positive regulator for TGF-β1 mRNA expression in PML-NBs) and increased TGF-β1 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.
authors.affiliation: Department of Pharmacology, The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University at Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacy, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, The 2nd Affiliated Hospital, Harbin Medical University at Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University at Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Qiu
authors.affiliation: Department of Pharmacology, The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University at Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University at Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Shang-Kun
authors.initials: SK
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University at Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Li
authors.affiliation: Department of Pharmacology, The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University at Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Mei-Tong
authors.initials: MT
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University at Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University at Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Jia-Xin
authors.initials: JX
authors.lastname: Wang
authors.affiliation: Department of Clinical Pharmacy, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, The 2nd Affiliated Hospital, Harbin Medical University at Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Ding
authors.affiliation: Department of Pharmacology, The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University at Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Yan-Xin
authors.initials: YX
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University at Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Chang-Jiang
authors.initials: CJ
authors.lastname: Dong
authors.affiliation: Department of Pharmacology, The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University at Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Xiao-Qi
authors.initials: XQ
authors.lastname: Shao
authors.affiliation: Department of Pharmacology, The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University at Harbin, Heilongjiang 150081, P.R. China. Electronic address: yangbf@ems.hrbmu.edu.cn.
authors.forename: Bao-Feng
authors.initials: BF
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University at Harbin, Heilongjiang 150081, P.R. China. Electronic address: cwf76928@aliyun.com.
authors.forename: Wen-Feng
authors.initials: WF
authors.lastname: Chu
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D003094:Collagen / Q000096:biosynthesis; D005355:Fibrosis; D020868:Gene Silencing; D051379:Mice; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D010087:Oxides / Q000494:pharmacology; D000071156:Promyelocytic Leukemia Protein / Q000378:metabolism*; D011485:Protein Binding; D058207:Sumoylation; D014157:Transcription Factors / Q000235:genetics*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D001152:Arsenicals; D009687:Nuclear Proteins; D010087:Oxides; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D003094:Collagen; D044763:Ubiquitin-Conjugating Enzymes; C486410:Rnf4 protein, mouse; D044767:Ubiquitin-Protein Ligases; D000098843:Ubiquitin-Conjugating Enzyme UBC9; D000077237:Arsenic Trioxide
keywords: PML; PML-NBs; Pin1; RNF4; SUMOylation; TGF-β1; UBC9; cardiac fibrosis