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| Content Provider | Springer Nature Link |
|---|---|
| Author | Daskoulidou, Nikoleta Zeng, Bo Berglund, Lisa M. Jiang, Hongni Chen, Gui Lan Kotova, Olga Bhandari, Sunil Ayoola, James Griffin, Steven Atkin, Stephen L. Gomez, Maria F. Xu, Shang Zhong |
| Copyright Year | 2014 |
| 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 Ca2+ store to Ca2+ 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 Ca2+ influx in vascular endothelial cells. The increased expression was also observed in the aortae from genetically modified Akita diabetic mice (C57BL/6-Ins2Akita/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 Ca2+-calcineurin-NFAT pathway is a novel mechanism causing abnormal Ca2+ homeostasis and endothelial dysfunction under hyperglycaemia. ORAI1-3 and STIM1-2 are ubiquitously expressed in vasculatures and upregulated by high glucose. Increased expression is confirmed in Akita (Ins2Akita/J) and STZ diabetic mice and patients. Upregulation mechanism is mediated by Ca2+/calcineurin/NFATc3 signalling. High glucose has no direct effects on ORAI1-3 channel activity and channel activation process. |
| Starting Page | 511 |
| Ending Page | 521 |
| Page Count | 11 |
| File Format | |
| ISSN | 09462716 |
| Journal | Journal of Molecular Medicine |
| Volume Number | 93 |
| Issue Number | 5 |
| e-ISSN | 14321440 |
| Language | English |
| Publisher | Springer Berlin Heidelberg |
| Publisher Date | 2014-12-05 |
| Publisher Place | Berlin/Heidelberg |
| Access Restriction | One Nation One Subscription (ONOS) |
| Subject Keyword | Hyperglycaemia Calcium channels ORAI STIM1 Diabetes mellitus Calcineurin NFATc transcription factors Molecular Medicine Human Genetics Internal Medicine |
| Content Type | Text |
| Resource Type | Article |
| Subject | Drug Discovery Molecular Medicine Genetics (clinical) |
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