Stromal interaction molecule 1 (STIM1) is a Ca2+ sensor that partners with Orai1 to elicit Ca2 entry in response to endoplasmic reticulum (ER) Ca2 store depletion. While store-operated Ca2 entry (SOCE) is important for maintaining ER Ca2 homeostasis in non-excitable cells, it is unclear what role it plays in the heart, although STIM1 is expressed in the heart and upregulated during disease. Here we analyzed transgenic mice with STIM1 overexpression in the heart to model the known increase of this protein in response to disease. As expected, STIM1 transgenic myocytes showed enhanced Ca2 entry following store depletion and partial co-localization with the type 2 ryanodine receptor (RyR2) within the sarcoplasmic reticulum (SR), as well as enrichment around the sarcolemma. STIM1 transgenic mice exhibited sudden cardiac death as early as 6weeks of age, while mice surviving past 12weeks of age developed heart failure with hypertrophy, induction of the fetal gene program, histopathology and mitochondrial structural alterations, loss of ventricular functional performance and pulmonary edema. Younger, pre-symptomatic STIM1 transgenic mice exhibited enhanced pathology following pressure overload stimulation or neurohumoral agonist infusion, compared to controls. Mechanistically, cardiac myocytes isolated from STIM1 transgenic mice displayed spontaneous Ca2 transients that were prevented by the SOCE blocker SKF-96365, increased L-type Ca<sup>2+</sup> channel (LTCC) current, and enhanced Ca2 spark frequency. Moreover, adult cardiac myocytes from STIM1 transgenic mice showed both increased diastolic Ca2 and maximal transient amplitude but no increase in total SR Ca2 load. Associated with this enhanced Ca2 profile was an increase in cardiac nuclear factor of activated T-cells (NFAT) and Ca2/calmodulin-dependent kinase II (CaMKII) activity. We conclude that STIM1 has an unexpected function in the heart where it alters communication between the sarcolemma and SR resulting in greater Ca2 flux and a leaky SR compartment.
Bibliographical noteFunding Information:
This work was supported by grants from the National Institutes of Health (to J.D. Molkentin and S.R. Houser). J.D. Molkentin was also supported by the Howard Hughes Medical Institute .
- Cardiac myocytes
- Heart failure