STIM1 elevation in the heart results in aberrant Ca2+ handling and cardiomyopathy

Correll, Robert N.; Goonasekera, Sanjeewa A.; Berlo, Jop H. van; Burr, Adam R.; Accornero, Federica; Zhang, Hongyu; Makarewich, Catherine A.; York, Allen J.; Sargent, Michelle A.; Chen, Xiongwen; Houser, Steven R.; Molkentin, Jeffery D.

doi:10.1016/j.yjmcc.2015.07.032

Cited by 99 publications

(114 citation statements)

References 35 publications

(65 reference statements)

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“…STIM/Orai contributions to electromechanical remodeling in hypertrophied hearts were studied in ventricular myocytes isolated from feline hearts with slow, progressive pressure overload (aortic banding). Myocytes isolated from hypertrophied hearts exhibited increased STIM1 expression, similar to previous reports 29 . Our novel findings include the observation that STIM1 was organized into puncta, indicating STIM1 activation in hypertrophied myocytes (Figure 1F).…”

Section: Discussionsupporting

confidence: 91%

“…STIM1 expression increases after pressure overload 19, 27, 29 and the resultant Ca 2+ influx is thought to be involved in the induction of pathological hypertrophy. STIM1 may be part of the fetal gene program that becomes reactivated during pathological stress and could contribute a pool of Ca 2+ that activates pathological hypertrophy signaling.…”

Section: Discussionmentioning

confidence: 99%

“…It is therefore not surprising that a physiological role for STIM and Orai in cardiac myocytes has not been defined. Yet, many independent groups have found STIM1 to be present in cardiac myocytes 27 , though there are conflicting reports on the function of STIM1 and SOCE in these cells 16, 28, 29 . In the diseased heart, SR Ca 2+ regulation is altered 11 and increased SOCE activity has been observed in rodent cardiac disease models.…”

Section: Introductionmentioning

confidence: 99%

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Role of STIM1 (Stromal Interaction Molecule 1) in Hypertrophy-Related Contractile Dysfunction

Troupes

Wallner

Borghetti

et al. 2017

Circulation Research

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Rationale Pathological increases in cardiac afterload result in myocyte hypertrophy with changes in myocyte electrical and mechanical phenotype. Remodeling of contractile and signaling Ca2+ occurs in pathological hypertrophy and is central to myocyte remodeling. Stromal Interaction Molecule 1 (STIM1) regulates Ca2+ signaling in many cell types by sensing low endoplasmic reticular Ca2+ levels and then coupling to plasma membrane Orai channels to induce a Ca2+ influx pathway. Previous reports suggest that STIM1 may play a role in cardiac hypertrophy but its role in electrical and mechanical phenotypic alterations are not well understood. Objective To define the contributions of STIM1-mediated Ca2+ influx on electrical and mechanical properties of normal and diseased myocytes, and to determine if Orai channels are obligatory partners for STIM1 in these processes using a clinically relevant large animal model of hypertrophy. Methods and Results Cardiac hypertrophy was induced by slow progressive pressure overload in adult cats. Hypertrophied myocytes had increased STIM1 expression and activity, which correlated with altered Ca2+ handling and action potential (AP) prolongation. Exposure of hypertrophied myocytes to the Orai channel blocker BTP2 caused in a reduction of AP duration and reduced diastolic Ca2+ spark rate. BTP2 had no effect on normal myocytes. Forced expression of STIM1 in cultured adult feline ventricular myocytes increased diastolic spark rate and prolonged AP duration. STIM1 expression produced an increase in the amount of Ca2+ stored within the sarcoplasmic reticulum and activated Ca2+/calmodulin-dependent protein kinase II. STIM1 expression also increased spark rates and induced spontaneous APs. STIM1 effects were eliminated by either BTP2 or by co-expression of a dominant negative Orai construct. Conclusions STIM1 can associate with Orai in cardiac myocytes to produce a Ca2+ influx pathway that can prolong the AP duration and load the SR and likely contributes to the altered electromechanical properties of the hypertrophied heart.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of STIM1 (Stromal Interaction Molecule 1) in Hypertrophy-Related Contractile Dysfunction

Troupes

Wallner

Borghetti

et al. 2017

Circulation Research

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“…SOCE has also emerged as a potential mechanism to alter Ca 2ϩ in the cardiomyocyte. It is greatly recognized that Ca 2ϩ entry through TRPC1, -C3, -C4, and -C6 channels and STIM1, by changing the fetal gene program governed by calcineurin/NFAT signaling, which is a characteristic of stressed cardiomyocytes, contributes to the pathogenesis of hypertrophy and HF (11,14,15,(21)(22)(23)(24)(25)(26). Additionally, many studies speculate the potential deleterious effect of SOCs in atrial and ventricular arrhythmias (27, 29, 31, 32).…”

Section: Discussionmentioning

confidence: 99%

Transient Receptor Potential Canonical (TRPC)/Orai1-dependent Store-operated Ca2+ Channels

Sabourin

Bartoli

Antigny

et al. 2016

Journal of Biological Chemistry

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Store-operated Ca2؉ entry (SOCE) has emerged as an important mechanism in cardiac pathology. However, the signals that up-regulate SOCE in the heart remain unexplored. Clinical trials have emphasized the beneficial role of mineralocorticoid receptor (MR) signaling blockade in heart failure and associated arrhythmias. Accumulated evidence suggests that the mineralocorticoid hormone aldosterone, through activation of its receptor, MR, might be a key regulator of Ca 2؉ influx in cardiomyocytes. We thus assessed whether and how SOCE involving transient receptor potential canonical (TRPC) and Orai1 channels are regulated by aldosterone/MR in neonatal rat ventricular cardiomyocytes. Molecular screening using qRT-PCR and Western blotting demonstrated that aldosterone treatment for 24 h specifically increased the mRNA and/or protein levels of Orai1, TRPC1, -C4, -C5, and stromal interaction molecule 1 through MR activation. These effects were correlated with a specific enhancement of SOCE activities sensitive to store-operated channel inhibitors (SKF-96365 and BTP2) and to a potent Orai1 blocker (S66) and were prevented by TRPC1, -C4, and Orai1 dominant negative mutants or TRPC5 siRNA. A mechanistic approach showed that up-regulation of serum-and glucocorticoid-regulated kinase 1 mRNA expression by aldosterone is involved in enhanced SOCE. Functionally, 24-h aldosterone-enhanced SOCE is associated with increased diastolic [Ca 2؉ ] i , which is blunted by store-operated channel inhibitors. Our study provides the first evidence that aldosterone promotes TRPC1-, -C4-, -C5-, and Orai1-mediated SOCE in cardiomyocytes through an MR and serum-and glucocorticoid-regulated kinase 1 pathway.The last discovered Ca 2ϩ channel family, transient receptor potential canonical (TRPC) 2 and Orai1 channels, is widely expressed, but the role of these channels and the modulation of their expression are not completely understood. Notably, the dysregulation of these important mediators of Ca 2ϩ -dependent signal transduction has been involved in a broad range of human diseases such as adenocarcinomas, type 2 diabetes and diabetic nephropathy, human proteinuric kidney disease focal and segmental glomerulosclerosis, severe immunodeficiency, congenital myopathy, chronic pulmonary disease, and ectodermal dysplasia (1, 2). Although predominantly thought of in the context of non-excitable cells, store-operated Ca 2ϩ entry (SOCE) by store-operated channels (SOCs) has recently emerged as a potential mechanism to alter Ca 2ϩ in the diseased cardiomyocyte. Although still under debate, the prime candidate proteins for SOCs encompass the TRPC channel(s) as non-selective cation channels as well as Orai1, the Ca 2ϩ selective pore-forming unit of the Ca 2ϩ release-activated Ca 2ϩ channel (3). Stromal interaction molecule 1 (STIM1) serves as a Ca 2ϩ sensor in the endoplasmic reticulum/sarcoplasmic reticulum (SR), clustering proximal to the plasma membrane to activate Orai1 (4) and TRPC channel(s) (5) when Ca 2ϩ stores are depleted. The seven isoforms of the T...

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“…A similar phenomenon has been reported in proliferative smooth muscle cells where STIM1 controls heteromultimers of Orai1 and Orai3 that are regulated by leucotrienes C4 9-11 . Interactions with less Ca 2+ selective channels, such as TRPCs, have also been suggested and STIM1 overexpression leads to dysregulated calcium transients 5, 12 . All together, these data indicate that STIM1 activates in response to stress and can interact with a diversity of plasma membrane channels that will however mediate highly localized Ca 2+ signals.…”

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confidence: 99%

Cardiac Stim1 Silencing Impairs Adaptive Hypertrophy and Promotes Heart Failure Through Inactivation of mTORC2/Akt Signaling

Bénard

Cacheux

et al. 2016

Circulation

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Background STromal Interaction Molecule 1 (STIM1) is a dynamic calcium signal transducer implicated in hypertrophic growth of cardiac myocytes. STIM1 is thought to act as an initiator of cardiac hypertrophic response at the level of the sarcolemma but the pathways underpinning this effect have not been examined. Methods and Results To determine the mechanistic role of STIM1 in cardiac hypertrophy and during the transition to heart failure, we manipulated STIM1 expression in mice cardiac myocytes using in vivo gene delivery of specific short hairpin RNAs. In three different models, we found that Stim1 silencing prevents the development of pressure-overload induced hypertrophy but also reverses pre-established cardiac hypertrophy. Reduction in STIM1 expression promoted a rapid transition to heart failure. We further showed that Stim1 silencing resulted in enhanced activity of the anti-hypertrophic and pro-apoptotic GSK-3β molecule. Pharmacological inhibition of GSK-3 was sufficient to reverse the cardiac phenotype observed after Stim1 silencing. At the level of ventricular myocytes, Stim1 silencing or inhibition abrogated the capacity for phosphorylation of AktS473, a hydrophic motif of Akt that is directly phosphorylated by mTORC2. We found that Stim1 silencing directly impaired mTORC2 kinase activity, which was supported by a direct interaction between STIM1 and Rictor, a specific component of mTORC2 complex. Conclusions These data support a model whereby STIM1 is critical to deactivate a key negative regulator of cardiac hypertrophy. In cardiac myocytes, STIM1 acts by tuning Akt kinase activity through activation of mTOR complex 2 (mTORC2), which further results in repression of GSK-3β activity.

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STIM1 elevation in the heart results in aberrant Ca2+ handling and cardiomyopathy

Cited by 99 publications

References 35 publications

Role of STIM1 (Stromal Interaction Molecule 1) in Hypertrophy-Related Contractile Dysfunction

Role of STIM1 (Stromal Interaction Molecule 1) in Hypertrophy-Related Contractile Dysfunction

Transient Receptor Potential Canonical (TRPC)/Orai1-dependent Store-operated Ca2+ Channels

Cardiac Stim1 Silencing Impairs Adaptive Hypertrophy and Promotes Heart Failure Through Inactivation of mTORC2/Akt Signaling

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