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Maria Gomez

Maria Gomez

Professor

Maria Gomez

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

Author

  • Nikoleta Daskoulidou
  • Bo Zeng
  • Lisa Berglund
  • Hongni Jiang
  • Gui-Lan Chen
  • Olga Kotova
  • Sunil Bhandari
  • James Ayoola
  • Steven Griffin
  • Stephen L. Atkin
  • Maria Gomez
  • Shang-Zhong Xu

Summary, in English

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.

Department/s

  • Cardiovascular Research - Immunity and Atherosclerosis
  • Diabetes - Molecular Metabolism
  • EXODIAB: Excellence in Diabetes Research in Sweden

Publishing year

2015

Language

English

Pages

511-521

Publication/Series

Journal of Molecular Medicine

Volume

93

Issue

5

Document type

Journal article

Publisher

Springer

Topic

  • Endocrinology and Diabetes
  • Cardiac and Cardiovascular Systems

Keywords

  • Hyperglycaemia
  • Calcium channels
  • ORAI
  • STIM1
  • Diabetes mellitus
  • Calcineurin
  • NFATc transcription factors

Status

Published

Research group

  • Cardiovascular Research - Immunity and Atherosclerosis
  • Diabetes - Molecular Metabolism

ISBN/ISSN/Other

  • ISSN: 1432-1440