In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 117, No. suppl_1 ( 2015-07-17)
Abstract:
Stromal interaction molecule 1 (STIM1) is a Ca2+ sensor that partners with Orai1, resulting in store-operated Ca2+ entry (SOCE) that is important for maintaining endoplasmic reticulum (ER) Ca2+ homeostasis. STIM1 is expressed in the heart and upregulated during disease, but its role in disease progression is unclear. In this study we used transgenic mice with STIM1 overexpression in the heart to model the known increase of this protein in response to cardiac disease. We found that STIM1 transgenic myocytes showed elevated Ca2+ entry following store depletion and STIM1 co-localized with the type 2 ryanodine receptor (RyR2) in the sarcoplasmic reticulum (SR). In addition, STIM1 transgenic mice exhibited sudden cardiac death as early as 6 weeks of age, while mice that survived past 12 weeks developed cardiac hypertrophy that progressed to heart failure, pulmonary edema, activation of the fetal gene program, alterations in mitochondrial structure, and reduced ventricular functional performance. When pre-symptomatic STIM1 transgenic mice were subjected to disease stimuli including pressure overload stimulation or neurohumoral agonist infusion, they showed greater pathology compared to control mice. STIM1 elevation also disrupted normal Ca2+ handling in cardiac myocytes, which showed spontaneous Ca2+ transients that could be inhibited by the SOCE blocker SKF-96265, as well as increased diastolic Ca2+ levels and elevated Ca2+ spark frequency. In keeping with this increase in Ca2+ cycling we also found that STIM1 elevation resulted in an increased baseline activity of cardiac nuclear factor of activated T-cells (NFAT) and Ca2+/calmodulin-dependent protein kinase II (CaMKII). This increased CaMKII activity did not, however, translate into additional RyR2 phosphorylation, suggesting that the augmented Ca2+ spark frequency observed was likely due to an elevation in SR Ca2+ load. Our results suggest that increased STIM1 expression elicits augmented Ca2+ entry, SR Ca2+ load and Ca2+ spark frequency, that leads to mitochondrial pathology and the induction of Ca2+ sensitive hypertrophic signaling pathways that contribute to cardiac disease.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/res.117.suppl_1.186
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2015
detail.hit.zdb_id:
1467838-X
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