PMID- 36209373
OWN - NLM
STAT- MEDLINE
DCOM- 20230116
LR  - 20230323
IS  - 1464-5491 (Electronic)
IS  - 0742-3071 (Linking)
VI  - 40
IP  - 2
DP  - 2023 Feb
TI  - UCMSCs-derived exosomal circHIPK3 promotes ulcer wound angiogenesis of diabetes 
      mellitus via miR-20b-5p/Nrf2/VEGFA axis.
PG  - e14968
LID - 10.1111/dme.14968 [doi]
AB  - AIMS: Experiments confirmed that circular RNAs contributed to the pathogenesis of 
      diabetic foot ulcers (DFUs). CircHIPK3 was upregulated in type 2 diabetes 
      mellitus (T2DM), but its role in DFU remained unknown. Our study aimed to 
      investigate the regulatory functions of exosomal circHIPK3 and its potential 
      mechanisms in DFU. METHODS: Exosomal size and distribution, marker proteins, and 
      circHIPK3 levels were evaluated by transmission electron microscope, ExoView 
      R200, western blot, and qRT-PCR. Flow cytometry, MTT, Wound healing assays, and 
      tube formation assays were used to assess the roles of exosomal circHIPK3 in high 
      glucose (HG)-treated human umbilical vein endothelial cells (HUVECs). The 
      relationships between Nrf2/VEGFA/circHIPK3 and miR-20b-5p, and between Nrf2 and 
      VEGFA were determined by luciferase reporter assay and RNA immunoprecipitation. 
      We used cell and mice models to investigate the mechanisms of exosomal circHIPK3 
      under diabetic conditions. RESULTS: CircHIPK3 was significantly upregulated in 
      exo-circHIPK3 rather than exo-vector. Exo-circHIPK3 remarkably inhibited cell 
      apoptosis but promoted cell proliferation, migration, and tube formation in 
      HG-treated HUVECs. Luciferase reporter and RIP assays showed that miR-20b-5p 
      targeted and inhibited Nrf2 and VEGFA, and circHIPK3 acted as a ceRNA of 
      miR-20b-5p to inhibit the binding to its downstream genes Nrf2 and VEGFA. 
      Mechanistically, circHIPK3 promoted cell proliferation, migration, and 
      angiogenesis via downregulating miR-20b-5p to upregulate Nrf2 and VEGFA. However, 
      the overexpressed miR-20b-5p could abolish the promoting effects of circHIPK3 
      overexpression on cell proliferation, migration, and tube formation under HG 
      conditions. CONCLUSION: UCMSCs-derived exosomal circHIPK3 protected HG-treated 
      HUVECs via miR-20b-5p/Nrf2/VEGFA axis. The exosomal circHIPK3 might be a 
      therapeutic candidate to treat DFU.
CI  - (c) 2022 Diabetes UK.
FAU - Liang, Zun-Hong
AU  - Liang ZH
AD  - Department of Burn & Skin Repair Surgery, Hainan General Hospital (Hainan 
      Affiliated Hospital of Hainan Medical University), Haikou, People's Republic of 
      China.
FAU - Lin, Shi-Shuai
AU  - Lin SS
AD  - Department of Burn & Skin Repair Surgery, Hainan General Hospital (Hainan 
      Affiliated Hospital of Hainan Medical University), Haikou, People's Republic of 
      China.
FAU - Pan, Nan-Fang
AU  - Pan NF
AD  - Department of Burn & Skin Repair Surgery, Hainan General Hospital (Hainan 
      Affiliated Hospital of Hainan Medical University), Haikou, People's Republic of 
      China.
FAU - Zhong, Guo-Yu
AU  - Zhong GY
AD  - Department of Burn & Skin Repair Surgery, Hainan General Hospital (Hainan 
      Affiliated Hospital of Hainan Medical University), Haikou, People's Republic of 
      China.
FAU - Qiu, Zhi-Yang
AU  - Qiu ZY
AD  - Department of Burn & Skin Repair Surgery, Hainan General Hospital (Hainan 
      Affiliated Hospital of Hainan Medical University), Haikou, People's Republic of 
      China.
FAU - Kuang, Shao-Jia
AU  - Kuang SJ
AD  - Department of Burn & Skin Repair Surgery, Hainan General Hospital (Hainan 
      Affiliated Hospital of Hainan Medical University), Haikou, People's Republic of 
      China.
FAU - Lin, Zhi-Hu
AU  - Lin ZH
AD  - Department of Burn & Skin Repair Surgery, Hainan General Hospital (Hainan 
      Affiliated Hospital of Hainan Medical University), Haikou, People's Republic of 
      China.
FAU - Zhang, Zhi
AU  - Zhang Z
AD  - Department of Burn and Plastic Surgery, Guangzhou Red Cross Hospital Affifiliated 
      to Jinan University, Guangzhou, People's Republic of China.
FAU - Pan, Yun-Chuan
AU  - Pan YC
AD  - Department of Burn & Skin Repair Surgery, Hainan General Hospital (Hainan 
      Affiliated Hospital of Hainan Medical University), Haikou, People's Republic of 
      China.
LA  - eng
GR  - 21A200256/Hainan Province Health Industry Scientific Research Project/
GR  - ZDYF2022SHFZ104/Key R&D Projects of Natural Science Foundation of Hainan 
      Province/
GR  - YSPTZX202028/The Hainan Provincial Academician Innovation Platform Scientific 
      Research Special Fund/
GR  - Ethics Committee of Hainan General Hospital/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221031
PL  - England
TA  - Diabet Med
JT  - Diabetic medicine : a journal of the British Diabetic Association
JID - 8500858
RN  - 0 (MicroRNAs)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (VEGFA protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
SB  - IM
MH  - Humans
MH  - Mice
MH  - Animals
MH  - *MicroRNAs/genetics/metabolism/pharmacology
MH  - NF-E2-Related Factor 2/genetics/metabolism/pharmacology
MH  - *Diabetes Mellitus, Type 2/complications/genetics/metabolism
MH  - Human Umbilical Vein Endothelial Cells/metabolism
MH  - Cell Proliferation/genetics
MH  - Vascular Endothelial Growth Factor A
OTO - NOTNLM
OT  - Asian diabetes
OT  - UCMSCs
OT  - circHIPK3
OT  - exosome
OT  - foot ulcer
OT  - miR-20b-5p
OT  - revascularization
EDAT- 2022/10/10 06:00
MHDA- 2023/01/17 06:00
CRDT- 2022/10/09 05:32
PHST- 2022/09/14 00:00 [revised]
PHST- 2022/06/21 00:00 [received]
PHST- 2022/10/07 00:00 [accepted]
PHST- 2022/10/10 06:00 [pubmed]
PHST- 2023/01/17 06:00 [medline]
PHST- 2022/10/09 05:32 [entrez]
AID - 10.1111/dme.14968 [doi]
PST - ppublish
SO  - Diabet Med. 2023 Feb;40(2):e14968. doi: 10.1111/dme.14968. Epub 2022 Oct 31.