Advanced

High glucose enhances store-operated calcium entry by upregulating ORAI/STIM via calcineurin-NFAT signalling

Daskoulidou, Nikoleta; Zeng, Bo; Berglund, Lisa LU ; Jiang, Hongni; Chen, Gui-Lan; Kotova, Olga LU ; Bhandari, Sunil; Ayoola, James; Griffin, Steven and Atkin, Stephen L., et al. (2015) In Journal of Molecular Medicine 93(5). p.511-521
Abstract
ORAI and stromal interaction molecule (STIM) are storeoperated channel molecules that play essential roles in human physiology through a coupling mechanism of internal Ca2+ store to Ca2+ influx. However, the roles of ORAI and STIMin vascular endothelial cells under diabetic conditions remain unknown. Here, we investigated expression and signalling pathways of ORAI and STIM regulated by high glucose or hyperglycaemia using in vitro cell models, in vivo diabetic mice and tissues from patients. We found that ORAI1-3 and STIM1-2 were ubiquitously expressed in human vasculatures. Their expression was upregulated by chronic treatment with high glucose (HG, 25 mM D-glucose), which was accompanied by enhanced store-operated Ca2+ influx in vascular... (More)
ORAI and stromal interaction molecule (STIM) are storeoperated channel molecules that play essential roles in human physiology through a coupling mechanism of internal Ca2+ store to Ca2+ influx. However, the roles of ORAI and STIMin vascular endothelial cells under diabetic conditions remain unknown. Here, we investigated expression and signalling pathways of ORAI and STIM regulated by high glucose or hyperglycaemia using in vitro cell models, in vivo diabetic mice and tissues from patients. We found that ORAI1-3 and STIM1-2 were ubiquitously expressed in human vasculatures. Their expression was upregulated by chronic treatment with high glucose (HG, 25 mM D-glucose), which was accompanied by enhanced store-operated Ca2+ influx in vascular endothelial cells. The increased expression was also observed in the aortae from genetically modified Akita diabetic mice (C57BL/6-Ins2(Akita)/J) and streptozocin-induced diabetic mice, and aortae from diabetic patients. HG-induced upregulation of ORAI and STIM genes was prevented by the calcineurin inhibitor cyclosporin A and NFATc3 siRNA. Additionally, in vivo treatment with the nuclear factor of activated T cells (NFAT) inhibitor A-285222 prevented the gene upregulation in Akita mice. However, HG had no direct effects on ORAI1-3 currents and the channel activation process through cytosolic STIM1 movement in the cells coexpressing STIM1-EYFP/ORAIs. We concluded that upregulation of STIM/ORAI through Ca2+-calcineurin-NFAT pathway is a novel mechanism causing abnormal Ca2+ homeostasis and endothelial dysfunction under hyperglycaemia. (Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Hyperglycaemia, Calcium channels, ORAI, STIM1, Diabetes mellitus, Calcineurin, NFATc transcription factors
in
Journal of Molecular Medicine
volume
93
issue
5
pages
511 - 521
publisher
Springer
external identifiers
  • wos:000353355200006
  • scopus:84939980055
ISSN
1432-1440
DOI
10.1007/s00109-014-1234-2
language
English
LU publication?
yes
id
9db1a343-b36e-4697-98fd-70aa2e02e948 (old id 5386128)
date added to LUP
2015-06-01 09:25:58
date last changed
2017-10-01 03:20:22
@article{9db1a343-b36e-4697-98fd-70aa2e02e948,
  abstract     = {ORAI and stromal interaction molecule (STIM) are storeoperated channel molecules that play essential roles in human physiology through a coupling mechanism of internal Ca2+ store to Ca2+ influx. However, the roles of ORAI and STIMin vascular endothelial cells under diabetic conditions remain unknown. Here, we investigated expression and signalling pathways of ORAI and STIM regulated by high glucose or hyperglycaemia using in vitro cell models, in vivo diabetic mice and tissues from patients. We found that ORAI1-3 and STIM1-2 were ubiquitously expressed in human vasculatures. Their expression was upregulated by chronic treatment with high glucose (HG, 25 mM D-glucose), which was accompanied by enhanced store-operated Ca2+ influx in vascular endothelial cells. The increased expression was also observed in the aortae from genetically modified Akita diabetic mice (C57BL/6-Ins2(Akita)/J) and streptozocin-induced diabetic mice, and aortae from diabetic patients. HG-induced upregulation of ORAI and STIM genes was prevented by the calcineurin inhibitor cyclosporin A and NFATc3 siRNA. Additionally, in vivo treatment with the nuclear factor of activated T cells (NFAT) inhibitor A-285222 prevented the gene upregulation in Akita mice. However, HG had no direct effects on ORAI1-3 currents and the channel activation process through cytosolic STIM1 movement in the cells coexpressing STIM1-EYFP/ORAIs. We concluded that upregulation of STIM/ORAI through Ca2+-calcineurin-NFAT pathway is a novel mechanism causing abnormal Ca2+ homeostasis and endothelial dysfunction under hyperglycaemia.},
  author       = {Daskoulidou, Nikoleta and Zeng, Bo and Berglund, Lisa and Jiang, Hongni and Chen, Gui-Lan and Kotova, Olga and Bhandari, Sunil and Ayoola, James and Griffin, Steven and Atkin, Stephen L. and Gomez, Maria and Xu, Shang-Zhong},
  issn         = {1432-1440},
  keyword      = {Hyperglycaemia,Calcium channels,ORAI,STIM1,Diabetes mellitus,Calcineurin,NFATc transcription factors},
  language     = {eng},
  number       = {5},
  pages        = {511--521},
  publisher    = {Springer},
  series       = {Journal of Molecular Medicine},
  title        = {High glucose enhances store-operated calcium entry by upregulating ORAI/STIM via calcineurin-NFAT signalling},
  url          = {http://dx.doi.org/10.1007/s00109-014-1234-2},
  volume       = {93},
  year         = {2015},
}