Chronic reduction of store operated Ca2+ entry is viable therapeutically but is associated with cardiovascular complications.
Academic Article
Overview
abstract
We generated a floxed STIM1 hypomorph mouse model with significant reduction in Ca2+ influx through SOCE, resulting in defective NFAT nuclear translocation, cytokine production, and inflammatory response. Hypomorph mice are viable and fertile, with no overt defects. Decreased SOCE in the hypomorph is due to poor translocation of the mutant STIM1 to ER-PM MCS resulting in less STIM1 puncta. The hypomorph have similar susceptibility to control to develop diabetes but exhibits tachycardia and hypertension. The hypertension is not due to increase VSM contractility or vascular remodeling. The tachycardia is not due to heart-specific defects but rather seems to be due to increased circulating catecholamines in the hypomorph. Therefore, long term SOCE inhibition is viable clinically if the cardiovascular defects can be managed clinically. ABSTRACT: Loss of function mutations in Store-operated Ca2+ entry (SOCE) are associated with severe pediatric disorders in humans, including combined immunodeficiency, anemia, 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, NFAT activation, and T cells 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 that 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. Graphical abstract legend Summary of the functional and signaling changes in the STIM1 hypomorph mouse model with the associated toxicities. This article is protected by copyright. All rights reserved.
