PMID- 36510823
OWN - NLM
STAT- MEDLINE
DCOM- 20230314
LR  - 20230323
IS  - 1464-5491 (Electronic)
IS  - 0742-3071 (Linking)
VI  - 40
IP  - 4
DP  - 2023 Apr
TI  - The vicious circle of UHRF1 down-regulation and KEAP1/NRF2/HO-1 pathway 
      impairment promotes oxidative stress-induced endothelial cell apoptosis in 
      diabetes.
PG  - e15026
LID - 10.1111/dme.15026 [doi]
AB  - BACKGROUND: Oxidative stress is recognized as a key factor in the induction of 
      endothelial dysfunction in diabetes. However, the specific mechanisms have not 
      been fully elucidated. We herein hypothesized that ubiquitin-like containing PHD 
      and RING finger domains 1 (UHRF1) might have a role in oxidative stress-induced 
      endothelial cell (EC) apoptosis in diabetes. METHODS: Western blot, qPCR, wound 
      healing assay, apoptosis assay, reactive oxygen species (ROS) detection, 
      dual-luciferase reporter assay, methylation-specific PCR, bisulfite sequencing 
      PCR and chromatin immunoprecipitation assay were performed. RESULTS: UHRF1 
      expression levels were significantly decreased in endothelial colony-forming 
      cells derived from peripheral blood of participants with type 2 diabetes compared 
      with individuals without diabetes. ECs treated with high glucose, palmitate or 
      hydrogen peroxide in vitro also exhibited decreased UHRF1 protein levels. 
      Silencing of UHRF1 led to decreased migration ability and increased apoptosis and 
      ROS production in ECs, which might be related to impaired Kelch-like 
      ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 
      (NRF2)/haeme oxygenase-1 pathway. Mechanistically, UHRF1 is closely implicated in 
      epigenetic regulation of chromatin modification status at KEAP1 genomic locus via 
      histone acetylation. NRF2 down-regulation in turn inhibits UHRF1 protein level, 
      which might be due to increased ROS generation. CONCLUSION: Diabetes-induced 
      oxidative stress can mediate down-regulation of UHRF1, which enhances ROS 
      production by regulating KEAP1/p-NRF2 pathway through histone acetylation and 
      might also form a self-perpetuating feedback loop with KEAP1/p-NRF2 to further 
      promote oxidative stress-induced apoptosis of ECs in diabetes.
CI  - (c) 2022 Diabetes UK.
FAU - Guo, Zi
AU  - Guo Z
AD  - Department of Endocrinology, The Third Xiangya Hospital and Diabetic Foot 
      Research Centre of Central South University, Changsha, China.
FAU - Wan, Xinxing
AU  - Wan X
AD  - Department of Endocrinology, The Third Xiangya Hospital and Diabetic Foot 
      Research Centre of Central South University, Changsha, China.
FAU - Luo, Yufang
AU  - Luo Y
AD  - Department of Endocrinology, The Third Xiangya Hospital and Diabetic Foot 
      Research Centre of Central South University, Changsha, China.
FAU - Liang, Fang
AU  - Liang F
AD  - Department of Endocrinology, The Third Xiangya Hospital and Diabetic Foot 
      Research Centre of Central South University, Changsha, China.
FAU - Jiang, Siwei
AU  - Jiang S
AD  - Department of Endocrinology, The Third Xiangya Hospital and Diabetic Foot 
      Research Centre of Central South University, Changsha, China.
FAU - Yuan, Xiuhong
AU  - Yuan X
AD  - Department of Clinical Psychology, The Third Xiangya Hospital of Central South 
      University, Changsha, China.
FAU - Mo, Zhaohui
AU  - Mo Z
AD  - Department of Endocrinology, The Third Xiangya Hospital and Diabetic Foot 
      Research Centre of Central South University, Changsha, China.
LA  - eng
GR  - 81970724/National Natural Science Foundation of China/
GR  - 2019JJ40454/Natural Science Foundation of Hunan Province/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221221
PL  - England
TA  - Diabet Med
JT  - Diabetic medicine : a journal of the British Diabetic Association
JID - 8500858
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (Histones)
RN  - 0 (KEAP1 protein, human)
RN  - EC 2.3.2.27 (UHRF1 protein, human)
RN  - 0 (CCAAT-Enhancer-Binding Proteins)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
SB  - IM
MH  - Humans
MH  - Reactive Oxygen Species/metabolism
MH  - Down-Regulation
MH  - *NF-E2-Related Factor 2/genetics/metabolism
MH  - Kelch-Like ECH-Associated Protein 1/genetics/metabolism
MH  - *Diabetes Mellitus, Type 2/genetics
MH  - Epigenesis, Genetic
MH  - Histones/genetics/metabolism
MH  - Oxidative Stress
MH  - Apoptosis
MH  - CCAAT-Enhancer-Binding Proteins/genetics/metabolism
MH  - Ubiquitin-Protein Ligases/genetics/metabolism
OTO - NOTNLM
OT  - KEAP1/NRF2
OT  - UHRF1
OT  - diabetes
OT  - endothelial cell
OT  - oxidative stress
EDAT- 2022/12/14 06:00
MHDA- 2023/03/15 06:00
CRDT- 2022/12/13 03:53
PHST- 2022/08/13 00:00 [received]
PHST- 2022/12/10 00:00 [accepted]
PHST- 2022/12/14 06:00 [pubmed]
PHST- 2023/03/15 06:00 [medline]
PHST- 2022/12/13 03:53 [entrez]
AID - 10.1111/dme.15026 [doi]
PST - ppublish
SO  - Diabet Med. 2023 Apr;40(4):e15026. doi: 10.1111/dme.15026. Epub 2022 Dec 21.