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

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

Authors

Nikoleta Daskoulidou

Shang Zhong Xu

Bo Zeng

Maria F. Gomez

Lisa M. Berglund

Stephen L. Atkin

Hongni Jiang

Steven Griffin

James Ayoola

Sunil Bhandari

Olga Kotova

Gui Lan Chen

Steven Griffin

Hongni Jiang

Lisa M. Berglund

Bo Zeng

Nikoleta Daskoulidou



Abstract

© 2014, Springer-Verlag Berlin Heidelberg. Abstract: ORAI and stromal interaction molecule (STIM) are store-operated channel molecules that play essential roles in human physiology through a coupling mechanism of internal Ca 2+ store to Ca 2+ influx. However, the roles of ORAI and STIM in 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 Ca 2+ 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 co-expressing STIM1-EYFP/ORAIs. We concluded that upregulation of STIM/ORAI through Ca 2+ -calcineurin-NFAT pathway is a novel mechanism causing abnormal Ca 2+ homeostasis and endothelial dysfunction under hyperglycaemia. Key message: ORAI1-3 and STIM1-2 are ubiquitously expressed in vasculatures and upregulated by high glucose.Increased expression is confirmed in Akita (Ins2 Akita /J) and STZ diabetic mice and patients.Upregulation mechanism is mediated by Ca 2+ /calcineurin/NFATc3 signalling.High glucose has no direct effects on ORAI1-3 channel activity and channel activation process.

Publication Date May 1, 2015
Journal Journal of molecular medicine
Print ISSN 0946-2716
Electronic ISSN 1432-1440
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 93
Issue 5
Pages 511-521
APA6 Citation Daskoulidou, N., Xu, S. Z., Zeng, B., Gomez, M. F., Berglund, L. M., Atkin, S. L., …Daskoulidou, N. (2015). High glucose enhances store-operated calcium entry by upregulating ORAI/STIM via calcineurin-NFAT signalling. Journal of Molecular Medicine, 93(5), 511-521. https://doi.org/10.1007/s00109-014-1234-2
DOI https://doi.org/10.1007/s00109-014-1234-2
Keywords Hyperglycaemia; Calcium channels; ORAI; STIM1; Diabetes mellitus; Calcineurin; NFATc transcription factors
Publisher URL http://link.springer.com/article/10.1007/s00109-014-1234-2
Copyright Statement ©2017 University of Hull
Additional Information Authors' accepted manuscript of article: Daskoulidou, N., Zeng, B., Berglund, L.M. et al. J Mol Med (2015) 93: 511. doi:10.1007/s00109-014-1234-2 The final publication is available at Springer via http://dx.doi.org/10.1007/s00109-014-1234-2

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