Critical Role for Stromal Interaction Molecule 1 in Cardiac Hypertrophy

Hulot, Jean‐Sébastien; Fauconnier, Jérémy; Ramanujam, Deepak; Chaanine, Antoine H.; Aubart, F. Cohen; Sassi, Yassine; Merkle, Sabine; Cazorla, Olivier; Ouillé, Aude; Dupuis, Morgan; Hadri, Lahouaria; Jeong, Dongtak; Mühlstedt, Silke; Schmitt, Joachim P.; Braun, Attila; Bénard, Ludovic; Saliba, Youakim; Laggerbauer, Bernhard; Nieswandt, Bernhard; Lacampagne, Alain; Hajjar, Roger J.; Lompré, Anne‐Marie; Engelhardt, Stefan

doi:10.1161/circulationaha.111.031229

Cited by 152 publications

(229 citation statements)

References 52 publications

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“…The existence of SOCE and expression of both STIM1 and Orai1 have also recently been shown to occur in HL-1 cardiomyocytes, an immortalized mouse atrial cell line (120). We and others have shown that in neonatal cardiomyocytes Ca 2ϩ store depletion induced STIM1 puncta formation, consistent with that seen in nonexcitable cells (37,153). We also demonstrated that in neonatal cardiomyocytes SOCE was highly selective for Ca 2ϩ , confirming that SOCE was primarily mediated by STIM1-Orai1 coupling rather than STIM1-TRPC1 (153).…”

Section: Orai1/trpcsupporting

confidence: 87%

“…The putative physiological and pathophysiological roles of SOCE and STIM1 that have been identified to date are summarized in Table 1. A number of studies have recently reported the presence of STIM1 in adult cardiomyocytes (37,59,153), and consistent with earlier evidence supporting a role for SOCE in regulating cardiac hypertrophy (38), STIM1 levels were shown to be increased in response to cardiac hypertrophy (37, 59). Nevertheless, despite evidence that SOCE exists in cardiomyocytes, its wider acceptance as a contributor to cardiomyocyte Ca 2ϩ homeostasis remains limited.…”

supporting

confidence: 78%

“…They also found that the high molecular weight STIM1 splice variant STIM1L also increased in response to hypertrophic stimuli; however, the significance of this finding remains to be determined. In addition, Hulot and colleagues (37) reported that STIM1 was both sufficient and necessary for cardiomyocyte hypertrophy both in vitro and more importantly in the adult heart in vivo; moreover, in vivo STIM1 gene silencing protected the heart from pressure overload-induced hypertrophy. These authors also showed that SOCE was significantly increased following cardiac hypertrophy, which was attenuated by STIM1 knockdown.…”

Section: Orai1/trpcmentioning

confidence: 99%

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STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

Collins

Zhu-Mauldin

Marchase

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

111

109

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Collins HE, Zhu-Mauldin X, Marchase RB, Chatham JC. STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology. Am J Physiol Heart Circ Physiol 305: H446 -H458, 2013. First published June 21, 2013 doi:10.1152/ajpheart.00104.2013.-Store-operated Ca 2ϩ entry (SOCE) is critical for Ca 2ϩ signaling in nonexcitable cells; however, its role in the regulation of cardiomyocyte Ca 2ϩ homeostasis has only recently been investigated. The increased understanding of the role of stromal interaction molecule 1 (STIM1) in regulating SOCE combined with recent studies demonstrating the presence of STIM1 in cardiomyocytes provides support that this pathway co-exists in the heart with the more widely recognized Ca 2ϩ handling pathways associated with excitation-contraction coupling. There is now substantial evidence that STIM1-mediated SOCE plays a key role in mediating cardiomyocyte hypertrophy, both in vitro and in vivo, and there is growing support for the contribution of SOCE to Ca 2ϩ overload associated with ischemia/reperfusion injury. Here, we provide an overview of our current understanding of the molecular regulation of SOCE and discuss the evidence supporting the role of STIM1/Orai1-mediated SOCE in regulating cardiomyocyte function.store-operated Ca 2ϩ entry; stromal interaction molecule 1; orai1; cardiomyocytes STORE-OPERATED CA 2ϩ ENTRY (SOCE), also known as capacitative calcium entry (CCE), is the major mechanism of Ca 2ϩ entry in nearly all nonexcitable cells (97, 99). In addition, it is increasingly recognized to co-exist with voltage-gated Ca 2ϩ channels in excitable cells, including neurons, skeletal muscle cells, and cardiomyocytes (1,38,45,83,121). In response to inositol 1,4,5-triphosphate (IP 3 )-(43) or ryanodine receptor (RyR)-mediated (3) Ca 2ϩ release from ER/SR stores, SOCE facilitates the influx of Ca 2ϩ from the extracellular space, resulting in a sustained increase in cytosolic Ca 2ϩ levels. Thus, although one of the roles of SOCE is to rapidly refill the depleted ER/SR stores, the subsequent sustained increase in cytosolic Ca 2ϩ also regulates numerous gene transcription pathways (33,50,151). Indeed, aberrant SOCE has been observed in a growing number of diseases including severe combined immunodeficiency, acute pancreatitis, and Alzheimer's disease (86).The integration of SOCE into well-established models of Ca 2ϩ homeostasis was hampered for many years by the lack of specific molecular mediators; even as recently as 2004 there was considerable controversy as to the specific mechanisms regulating SOCE (90, 113). However, in 2005, stromal interaction molecule 1 (STIM1) was found to localize to the ER/SR membrane and shown to function as a primary mediator of SOCE (54, 102). The putative physiological and pathophysiological roles of SOCE and STIM1 that have been identified to date are summarized in Table 1. A number of studies have recently reported the presence of STIM1 in adult cardiomyocytes (37,59,153), and consistent with earlier evidence supporting a rol...

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Section: Orai1/trpcsupporting

confidence: 87%

supporting

confidence: 78%

Section: Orai1/trpcmentioning

confidence: 99%

See 1 more Smart Citation

STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

Collins

Zhu-Mauldin

Marchase

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

111

109

View full text Add to dashboard Cite

show abstract

“…Previously, research in rodent models has demonstrated that SOCE, STIM1, and Orai1 play crucial roles in the development of cardiomyocyte hypertrophy [8][9][10], whereas NO, cGMP, and PKG exert antihypertrophic effect [6,11,34]. However, one of the challenges in exploring mechanistic insight of Orai1 and/or NO-cGMP-PKG effect is lack of human cardiomyocytes for research.…”

Section: Discussionmentioning

confidence: 99%

“…A decrease of Ca 21 in sarco/endoplasmic reticulum causes STIM1 oligomerization and relocalization to the regions immediately underneath the plasma membrane, where it interacts with Orai1 to induce Ca 21 entry [8]. Interestingly, both STIM1 and Orai1 are reported to play essential roles in promoting cardiomyocyte hypertrophy [9,10].…”

Section: Introductionmentioning

confidence: 99%

Nitric Oxide-cGMP-PKG Pathway Acts on Orai1 to Inhibit the Hypertrophy of Human Embryonic Stem Cell-Derived Cardiomyocytes

Wang

Zhang

et al. 2015

Stem Cells

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Cardiac hypertrophy is an abnormal enlargement of heart muscle. It frequently results in congestive heart failure, which is a leading cause of human death. Previous studies demonstrated that the nitric oxide (NO), cyclic GMP (cGMP), and protein kinase G (PKG) signaling pathway can inhibit cardiac hypertrophy and thus improve cardiac function. However, the underlying mechanisms are not fully understood. Here, based on the human embryonic stem cell-derived cardiomyocyte (hESC-CM) model system, we showed that Orai1, the pore-forming subunit of store-operated Ca 21 entry (SOCE), is the downstream effector of PKG. Treatment of hESC-CMs with an a-adrenoceptor agonist phenylephrine (PE) caused a marked hypertrophy, which was accompanied by an upregulation of Orai1. Moreover, suppression of Orai1 expression/activity using Orai1-siRNAs or a dominant-negative construct Orai1 G98A inhibited the hypertrophy, suggesting that Orai1-mediated SOCE is indispensable for the PE-induced hypertrophy of hESC-CMs. In addition, the hypertrophy was inhibited by NO and cGMP via activating PKG. Importantly, substitution of Ala for Ser 34 in Orai1 abolished the antihypertrophic effects of NO, cGMP, and PKG. Furthermore, PKG could directly phosphorylate Orai1 at Ser 34 and thus prevent Orai1-mediated SOCE. Together, we conclude that NO, cGMP, and PKG inhibit the hypertrophy of hESC-CMs via PKG-mediated phosphorylation on Orai1-Ser-34. These results provide novel mechanistic insights into the action of cGMP-PKG-related antihypertrophic agents, such as NO donors and sildenafil. STEM CELLS 2015;33:2973-2984 SIGNIFICANCE STATEMENTCardiac hypertrophy is an abnormal enlargement of cardiomyocytes. It contributes to congestive heart failure. Nitric oxide donors and cGMP-phosphodiesterase inhibitors have been used in clinical trials to treat cardiac hypertrophy. However, the underlying mechanisms of these agents are not fully understood. Here, with the use of human embryonic stem cell-derived cardiomyocytes as the model, we uncovered a novel mechanism underlying the inhibitory effect of these agents on cardiac hypertrophy. We found that nitric oxide and cGMP, via protein kinase G-mediated phosphorylation on Orai1 proteins, inhibit the cardiomyocyte hypertrophy. This study provides novel mechanistic insights into the action of nitric oxide-related anti-hypertrophic agents.

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Store‐Operated Calcium Entry Mediated by ORAI and STIM

Nguyen

Han

Cao

et al. 2018

Comprehensive Physiology

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The calcium release-activated calcium (CRAC) channel, composed of ORAI and stromal interaction molecules (STIM), represents a prototypical example of store-operated calcium entry in mammals. The ORAI-STIM signaling occurs at membrane contact sites formed by close appositions between the endoplasmic reticulum (ER) and the plasma membrane. ORAI1 is a four-pass transmembrane protein that forms a highly calcium-selective ion channel in the plasma membrane. STIM1 is an ER-resident, a single-pass transmembrane protein that serves as a calcium sensor within the ER lumen and a potent activator of ORAI1 calcium channels. The intricate interplay between ORAI and STIM controls calcium entry into cells to regulate a myriad of physiological processes. We highlight herein the current knowledge on the structure-function relationship of CRAC channel, with a focus on key structural elements that mediate STIM1 conformational switch and the dynamic coupling between STIM1 and ORAI1. Furthermore, we discuss the physiological roles of STIM-ORAI signaling in various tissues and organs, as well as major pathological conditions arising from loss- or gain-of-function mutations in human ORAI1 and STIM1. © 2017 American Physiological Society. Compr Physiol 8:981-1002, 2018.

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Critical Role for Stromal Interaction Molecule 1 in Cardiac Hypertrophy

Cited by 152 publications

References 52 publications

STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

Nitric Oxide-cGMP-PKG Pathway Acts on Orai1 to Inhibit the Hypertrophy of Human Embryonic Stem Cell-Derived Cardiomyocytes

Store‐Operated Calcium Entry Mediated by ORAI and STIM

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