Yu, Fang;
Courjaret, Raphael;
Elmi, Asha;
Adap, Ethel Alcantara;
Orie, Nelson N;
Zghyer, Fawzi;
Hubrack, Satanay;
... Machaca, Khaled; + view all
(2022)
Chronic reduction of store operated Ca2+ entry is viable therapeutically but is associated with cardiovascular complications.
The Journal of Physiology
, 600
(22)
pp. 4827-4848.
10.1113/JP283811.
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Abstract
Loss of function mutations in store-operated Ca2+ entry (SOCE) are associated with severe paediatric disorders in humans, including combined immunodeficiency, anaemia, thrombocytopenia, anhidrosis and muscle hypotonia. Given its central role in immune cell activation, SOCE has been a therapeutic target for autoimmune and inflammatory diseases. Treatment for such chronic diseases would require prolonged SOCE inhibition. It is, however, unclear whether chronic SOCE inhibition is viable therapeutically. Here we address this issue using a novel genetic mouse model (SOCE hypomorph) with deficient SOCE, nuclear factor of activated T cells activation, and T cell cytokine production. SOCE hypomorph mice develop and reproduce normally and do not display muscle weakness or overt anhidrosis. They do, however, develop cardiovascular complications, including hypertension and tachycardia, which we show are due to increased sympathetic autonomic nervous system activity and not cardiac or vascular smooth muscle autonomous defects. These results assert that chronic SOCE inhibition is viable therapeutically if the cardiovascular complications can be managed effectively clinically. They further establish the SOCE hypomorph line as a genetic model to define the therapeutic window of SOCE inhibition and dissect toxicities associated with chronic SOCE inhibition in a tissue-specific fashion.
| Type: | Article |
|---|---|
| Title: | Chronic reduction of store operated Ca2+ entry is viable therapeutically but is associated with cardiovascular complications |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1113/JP283811 |
| Publisher version: | https://doi.org/10.1113/jp283811 |
| Language: | English |
| Additional information: | Copyright © 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society. This is an open access article under the terms of the Creative Commons Attribution License, https://creativecommons.org/licenses/by/4.0/, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | Hypertension; immunodeficiency; STIM1; store-operated Ca2+ entry; tachycardia |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10207558 |
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