PMID- 35270021
OWN - NLM
STAT- MEDLINE
DCOM- 20220408
LR  - 20220408
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 23
IP  - 5
DP  - 2022 Mar 7
TI  - Hyperglycemia Promotes Endothelial Cell Senescence through AQR/PLAU Signaling 
      Axis.
LID - 10.3390/ijms23052879 [doi]
LID - 2879
AB  - Hyperglycemia is reported to accelerate endothelial cell senescence that 
      contributes to diabetic complications. The underlying mechanism, however, remains 
      elusive. We previously demonstrated AQR as a susceptibility gene for type 2 
      diabetes mellitus (T2DM) and showed that it was increased in multiple tissues in 
      models with T2DM or metabolic syndrome. This study aimed to investigate the role 
      of AQR in hyperglycemia-induced senescence and its underlying mechanism. Here, we 
      retrieved several datasets of the aging models and found the expression of AQR 
      was increased by high glucose and by aging across species, including C. elegans 
      (whole-body), rat (cardiac tissues), and monkey (blood). we validated the 
      increased AQR expression in senescent human umbilical vein endothelial cells 
      (HUVECs). When overexpressed, AQR promoted the endothelial cell senescence, 
      confirmed by an increased number of cells stained with senescence-associated 
      beta-galactosidase and upregulation of CDKN1A (P21) as well as the prohibited 
      cellular colony formation and G2/M phase arrest. To explore the mechanism by 
      which AQR regulated the cellular senescence, transcriptomic analyses of HUVECs 
      with the overexpression and knockdown of the AQR were performed. We identified 52 
      co-expressed genes that were enriched, in the terms of plasminogen activation, 
      innate immunity, immunity, and antiviral defense. Among co-expressed genes, PLAU 
      was selected to evaluate its contribution to senescence for its highest strength 
      in the enrichment of the biological process. We demonstrated that the knockdown 
      of PLAU rescued senescence-related phenotypes, endothelial cell activation, and 
      inflammation in models induced by AQR or TNF-alpha. These findings, for the first 
      time, indicate that AQR/PLAU is a critical signaling axis in the modulation of 
      endothelial cell senescence, revealing a novel link between hyperglycemia and 
      vascular dysfunction. The study may have implications in the prevention of 
      premature vascular aging associated with T2DM.
FAU - Wan, Yiqi
AU  - Wan Y
AD  - Aging and Vascular Diseases, Human Aging Research Institute (HARI), School of 
      Life Science, Jiangxi Key Laboratory of Human Aging, Nanchang University, 
      Nanchang 330031, China.
FAU - Liu, Zhirui
AU  - Liu Z
AD  - Aging and Vascular Diseases, Human Aging Research Institute (HARI), School of 
      Life Science, Jiangxi Key Laboratory of Human Aging, Nanchang University, 
      Nanchang 330031, China.
FAU - Wu, Andong
AU  - Wu A
AD  - Aging and Vascular Diseases, Human Aging Research Institute (HARI), School of 
      Life Science, Jiangxi Key Laboratory of Human Aging, Nanchang University, 
      Nanchang 330031, China.
FAU - Khan, Abdul Haseeb
AU  - Khan AH
AUID- ORCID: 0000-0003-4845-7774
AD  - Aging and Vascular Diseases, Human Aging Research Institute (HARI), School of 
      Life Science, Jiangxi Key Laboratory of Human Aging, Nanchang University, 
      Nanchang 330031, China.
FAU - Zhu, Ying
AU  - Zhu Y
AUID- ORCID: 0000-0003-4259-5201
AD  - Aging and Vascular Diseases, Human Aging Research Institute (HARI), School of 
      Life Science, Jiangxi Key Laboratory of Human Aging, Nanchang University, 
      Nanchang 330031, China.
FAU - Ding, Shuangjin
AU  - Ding S
AD  - Aging and Vascular Diseases, Human Aging Research Institute (HARI), School of 
      Life Science, Jiangxi Key Laboratory of Human Aging, Nanchang University, 
      Nanchang 330031, China.
FAU - Li, Xueer
AU  - Li X
AD  - Aging and Vascular Diseases, Human Aging Research Institute (HARI), School of 
      Life Science, Jiangxi Key Laboratory of Human Aging, Nanchang University, 
      Nanchang 330031, China.
FAU - Zhao, Ya
AU  - Zhao Y
AD  - Aging and Vascular Diseases, Human Aging Research Institute (HARI), School of 
      Life Science, Jiangxi Key Laboratory of Human Aging, Nanchang University, 
      Nanchang 330031, China.
FAU - Dai, Ximo
AU  - Dai X
AD  - Aging and Vascular Diseases, Human Aging Research Institute (HARI), School of 
      Life Science, Jiangxi Key Laboratory of Human Aging, Nanchang University, 
      Nanchang 330031, China.
FAU - Zhou, Jin
AU  - Zhou J
AD  - Aging and Vascular Diseases, Human Aging Research Institute (HARI), School of 
      Life Science, Jiangxi Key Laboratory of Human Aging, Nanchang University, 
      Nanchang 330031, China.
FAU - Liu, Jiankun
AU  - Liu J
AD  - Aging and Vascular Diseases, Human Aging Research Institute (HARI), School of 
      Life Science, Jiangxi Key Laboratory of Human Aging, Nanchang University, 
      Nanchang 330031, China.
FAU - Li, Yuanyuan
AU  - Li Y
AD  - Aging and Vascular Diseases, Human Aging Research Institute (HARI), School of 
      Life Science, Jiangxi Key Laboratory of Human Aging, Nanchang University, 
      Nanchang 330031, China.
FAU - Gong, Xueting
AU  - Gong X
AD  - Aging and Vascular Diseases, Human Aging Research Institute (HARI), School of 
      Life Science, Jiangxi Key Laboratory of Human Aging, Nanchang University, 
      Nanchang 330031, China.
FAU - Liu, Man
AU  - Liu M
AD  - Aging and Vascular Diseases, Human Aging Research Institute (HARI), School of 
      Life Science, Jiangxi Key Laboratory of Human Aging, Nanchang University, 
      Nanchang 330031, China.
FAU - Tian, Xiao-Li
AU  - Tian XL
AUID- ORCID: 0000-0002-0868-7025
AD  - Aging and Vascular Diseases, Human Aging Research Institute (HARI), School of 
      Life Science, Jiangxi Key Laboratory of Human Aging, Nanchang University, 
      Nanchang 330031, China.
LA  - eng
GR  - 2020YFC2002900/Ministry of Science and Technology/
GR  - 81630034/National Natural Science Foundation of China/
GR  - 20192ACB70002, 20181ACB20017, and 20181BCD40001/Jiangxi Science and Technology 
      Department/
PT  - Journal Article
DEP - 20220307
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
SB  - IM
MH  - Animals
MH  - *Biological Phenomena
MH  - Caenorhabditis elegans
MH  - Cells, Cultured
MH  - Cellular Senescence/genetics
MH  - *Diabetes Mellitus, Type 2
MH  - Human Umbilical Vein Endothelial Cells/metabolism
MH  - Humans
MH  - *Hyperglycemia/genetics/metabolism
MH  - Rats
PMC - PMC8911151
OTO - NOTNLM
OT  - AQR
OT  - PLAU
OT  - diabetes
OT  - endothelial senescence
OT  - inflammation
COIS- The authors declare no conflict of interest.
EDAT- 2022/03/11 06:00
MHDA- 2022/04/09 06:00
PMCR- 2022/03/07
CRDT- 2022/03/10 15:37
PHST- 2022/01/14 00:00 [received]
PHST- 2022/02/23 00:00 [revised]
PHST- 2022/03/02 00:00 [accepted]
PHST- 2022/03/10 15:37 [entrez]
PHST- 2022/03/11 06:00 [pubmed]
PHST- 2022/04/09 06:00 [medline]
PHST- 2022/03/07 00:00 [pmc-release]
AID - ijms23052879 [pii]
AID - ijms-23-02879 [pii]
AID - 10.3390/ijms23052879 [doi]
PST - epublish
SO  - Int J Mol Sci. 2022 Mar 7;23(5):2879. doi: 10.3390/ijms23052879.