Abstract 16836: STIM1-Mediated Store-Operated Calcium Entry: a Friend or Foe in the Adult Heart
Voltage dependent Ca2+ entry is widely considered to be the primary Ca2+ entry pathway in cardiomyocytes; however, we and others have shown that both store-operated Ca2+ entry (SOCE) and its molecular mediator (the ER/SR Ca2+ sensor, Stromal interaction molecule 1 [STIM1]) exist in neonatal and adult cardiomyocytes. To date, the only known role of STIM1-mediated SOCE in the heart is regarding hypertrophic signaling. Remarkably little is known of the physiological role of STIM1 in the heart. Therefore, the goal of this study was to use a novel cardiomyocyte-restricted STIM1 knockout (crSTIM1-KO) mouse model to evaluate the role of STIM1 in normal cardiomyocyte function. Cardiac function was assessed by serial echocardiography every 4 weeks, from 12 weeks to 36 weeks of age in crSTIM1-KO and WT mice. Up to 20 weeks of age, no significant differences in function were observed; however, by 36 weeks there was a significant decline in % ejection fraction (56.48 ± 2.28 v 33.59 ± 4.37; p < 0.001) and % fractional shortening (29.18 ± 1.49 v 16.18 ± 2.23; p < 0.001) in crSTIM1-KO compared with WT controls. This decline in function was associated with a significant increase in diastolic LV volume (72.74 μl ± 10.55 v 110.80 μl ± 11.90; p < 0.01), and a reduction in diastolic LV wall thickness (0.91 mm ± 0.07 v 0.65 mm ± 0.02; p < 0.001) with no change in LV mass (111.98 mg ± 6.43 v 111.12 mg ± 7.26; p > 0.05). Histological analysis indicated marked inflammatory infiltrate in crSTIM1-KO hearts as early as 20 weeks of age, which was absent in WT hearts; this became progressively worse by 36 weeks. Unbiased gene expression arrays on hearts from 12 weeks of age revealed that only 15 genes were differentially expressed between crSTIM-1 KO and WT hearts (including increases in genes for SERCA and sarcolipin). The relatively small number of altered genes suggests that the functional decline seen between 20 and 36 weeks is not due to developmental adaptation following deletion of STIM1. These data demonstrate for the first time that STIM1 is essential for maintaining normal cardiac function in the adult heart.
- © 2013 by American Heart Association, Inc.