STIM1-dependent Ca2+ microdomains are required for myofilament remodeling and signaling in the heart

Abstract

In non-excitable cells stromal interaction molecule 1 (STIM1) is a key element in the generation of Ca2+ signals that lead to gene expression, migration and cell proliferation. A growing body of literature suggests that STIM1 plays a key role in the development of pathological cardiac hypertrophy. However, the precise mechanisms involving STIM-dependent Ca2+ signaling in the heart are not clearly established. Here, we have investigated the STIM1-associated Ca2+ signals in cardiomyocytes and their relevance to pathological cardiac remodeling. We show that mice with inducible, cardiac-restricted, ablation of STIM1 exhibited left ventricular reduced contractility, which was corroborated by impaired single cell contractility. The spatial properties of STIM1-dependent Ca2+ signals determine restricted Ca2+ microdomains that regulate myofilament remodeling and activate spatially segregated pro-hypertrophic factors. Indeed, mice lacking STIM1 showed less adverse structural remodeling in response to pressure overload-induced cardiac hypertrophy. These results highlight how STIM1-dependent Ca2+ microdomains have a major impact on intracellular Ca2+ homeostasis, cytoskeletal remodeling and cellular signaling, even when excitation-contraction coupling is present.

Suppression of store-operated calcium entry causes dilated cardiomyopathy of the Drosophila heart

“…For example, siRNA knockdown of STIM1 in freshly isolated neonatal rat ventricular myocytes led to a significant reduction of the caffeine-releasable SR Ca 2+ pools (Voelkers et al, 2010), whereas SR Ca 2+ store content was unchanged in adult cardiomyocytes isolated from STIM1 deleted mouse hearts compared to controls (Parks et al, 2016). These STIM1 deleted hearts also exhibited dilated cardiomyopathy, suggesting that SR Ca 2+ store depletion may not be a direct cause of heart failure when SOCE is suppressed.…”

“…In light of this strong evidence that enhanced SOCE can drive pathological responses in cardiomyocytes, an important question remains: what is the role of SOCE in healthy cardiomyocytes and normal heart physiology? In support of the concept that SOCE is essential for healthy cardiac function, two independent studies have shown that cardiomyocyte restricted STIM1 deletion in mice results in marked left ventricular dilation and reduced ejection fraction in adult hearts (Collins et al, 2014;Horton et al, 2014;Parks et al, 2016). Decreased cardiac function was concomitant with indications of ER stress and changes in cardiomyocyte mitochondrial morphology (Collins et al, 2014), as well as altered contractile Ca 2+ transients and myofibril organization (Parks et al, 2016).…”

“…In support of the concept that SOCE is essential for healthy cardiac function, two independent studies have shown that cardiomyocyte restricted STIM1 deletion in mice results in marked left ventricular dilation and reduced ejection fraction in adult hearts (Collins et al, 2014;Horton et al, 2014;Parks et al, 2016). Decreased cardiac function was concomitant with indications of ER stress and changes in cardiomyocyte mitochondrial morphology (Collins et al, 2014), as well as altered contractile Ca 2+ transients and myofibril organization (Parks et al, 2016). In addition, Orai1 suppression in zebrafish embryos resulted in reduced fractional shortening and severe heart failure (Volkers et al, 2012).…”

“…Results from mouse models demonstrate that STIM1 suppression results in agedependent cardiomyopathy and heart failure in adults (Collins et al, 2014;Parks et al, 2016), whereas severe heart failure was evident during embryogenesis in zebrafish with Orai1 suppression (Volkers et al, 2012). We therefore sought to determine whether cardiomyopathy caused by SOCE suppression in Drosophila occurs in larvae, prior to the adult life cycle stage.…”

“…Numerous studies strongly suggest that SOCE contributes to the pathogenesis of pathological cardiac hypertrophy, whereby heart muscle mass increases in response to stressors such as hypertension or valve dysfunctions. For example, induction of cardiac hypertrophy by pressure overload results in upregulation of STIM1 and Orai1 expression in mouse cardiac tissue, and cardiomyocyte-specific STIM1 and Orai1 suppression attenuates the hypertrophic response (Benard et al, 2016;Hulot et al, 2011;Luo et al, 2012;Parks et al, 2016). Similarly, suppression of STIM1 or Orai1 in rodent cardiomyocytes attenuates phenylephrine and endothelin-1 induced hypertrophy (Hulot et al, 2011;Luo et al, 2012;Voelkers et al, 2010).…”