STIM1 Restores Coronary Endothelial Function in Type 1 Diabetic Mice

Estrada, Irene; Donthamsetty, Reshma; Debski, Patryk; Zhou, Miou; Zhang, Shenyuan L.; Yuan, Jason X.‐J.; Han, Wenlong; Makino, Ayako

doi:10.1161/circresaha.112.275743

Cited by 55 publications

(68 citation statements)

References 50 publications

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“…In contrast, STIM1/Orai1-dependent SOCe is required for T and B cell activation (61), and mutations in STIM1 result in immunodeficiency and autoimmune syndromes (62). Recently, a type 1 diabetic mouse model study reported that downregulation of STIM1 and SERCA3 in coronary ECs enhanced the ER Ca 2+ leak and store depletion (27). This is in agreement with our work demonstrating a requirement of STIM1 for ER Ca 2+ homeostasis.…”

Section: Discussionsupporting

confidence: 89%

“…Notably, ER Ca 2+ levels were lower in Stim1 ΔEC when compared with VE-Cre or Stim1 fl/fl mice ECs, as measured by store depletion using thapsigargin ( Figure 1F). Our results are consistent with lower ER Ca 2+ levels in ECs derived from hyperglycemic mice due to the downregulation of STIM1 and SERCA3 expression (27). To examine whether loss of STIM1 alters NOX2-mediated ROS production, we measured NOX2 protein expression and superoxide production in Stim1 ΔEC ECs.…”

Section: Ec-specific Stim1supporting

confidence: 85%

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Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation

Gandhirajan¹,

Meng²,

et al. 2013

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During sepsis, acute lung injury (ALI) results from activation of innate immune cells and endothelial cells by endotoxins, leading to systemic inflammation through proinflammatory cytokine overproduction, oxidative stress, and intracellular Ca 2+ overload. Despite considerable investigation, the underlying molecular mechanism(s) leading to LPS-induced ALI remain elusive. To determine whether stromal interaction molecule 1-dependent (STIM1-dependent) signaling drives endothelial dysfunction in response to LPS, we investigated oxidative and STIM1 signaling of EC-specific Stim1-knockout mice. Here we report that LPSmediated Ca 2+ oscillations are ablated in ECs deficient in Nox2, Stim1, and type II inositol triphosphate receptor (Itpr2). LPS-induced nuclear factor of activated T cells (NFAT) nuclear accumulation was abrogated by either antioxidant supplementation or Ca 2+ chelation. Moreover, ECs lacking either Nox2 or Stim1 failed to trigger store-operated Ca 2+ entry (SOCe) and NFAT nuclear accumulation. LPS-induced vascular permeability changes were reduced in EC-specific Stim1 -/-mice, despite elevation of systemic cytokine levels. Additionally, inhibition of STIM1 signaling prevented receptor-interacting protein 3-dependent (RIP3-dependent) EC death. Remarkably, BTP2, a small-molecule calcium release-activated calcium (CRAC) channel blocker administered after insult, halted LPS-induced vascular leakage and pulmonary edema. These results indicate that ROS-driven Ca 2+ signaling promotes vascular barrier dysfunction and that the SOCe machinery may provide crucial therapeutic targets to limit sepsis-induced ALI.

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Section: Discussionsupporting

confidence: 89%

Section: Ec-specific Stim1supporting

confidence: 85%

Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation

Gandhirajan¹,

Meng²,

et al. 2013

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“…Estrada et al (19) demonstrated that endothelial cells from diabetic mice were found to have reduced ER Ca 2ϩ and significantly decreased STIM1 protein levels compared with nondiabetic mice; subsequent overexpression of STIM1 restored ER Ca 2ϩ levels and improved endothelium-dependent relaxation of diabetic coronary arteries. They also found that endothelial cells from normal animals exposed to hyperglycemia exhibited changes in ER Ca 2ϩ and STIM1 levels similar to those seen in response to diabetes (19).…”

Section: Potential Role For Stim1-mediated Soce In Ischemia/reperfusimentioning

confidence: 64%

“…A recent study of endothelial cell function demonstrated that a decrease in STIM1 protein levels observed in response to hyperglycemia was associated with a decrease in total ER Ca 2ϩ content, and restoration of STIM1 protein to normal levels restored ER Ca 2ϩ levels (19). Although it remains to be determined whether this is also the case in cardiomyocytes, this study raises the possibility that, in addition to contributing to ␣-adrenergic and hypertrophic signaling, STIM1 could also contribute to the regulation of basal SR/ER Ca 2ϩ levels in cardiomyocytes.…”

Section: Orai1/trpcmentioning

confidence: 99%

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

108

102

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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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“…Contrary to the Daskoulidou study, Estrada et al recently reported that STIM1 protein expression was significantly reduced in coronary endothelial cells from STZ-diabetic mice. 114 The decrease in STIM1 protein abundance impaired ER Ca 2þ refilling by disrupting the interaction between STIM1 and the ER/SR Ca 2þ -ATPase, and consequently attenuated endothelium-dependent relaxation in diabetic coronary arteries. 114 Importantly, the endothelial dysfunction could be rescued by restoring the expression level of STIM1 in diabetic coronary endothelial cells.…”

Section: Soce and Diabetic Vasculopathymentioning

confidence: 97%

Store-operated calcium entry and diabetic complications

Chaudhari

2015

Exp Biol Med (Maywood)

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Store-operated Ca 2þ entry (SOCE) is mediated by the store-operated Ca 2þ channel (SOC) that opens upon depletion of internal Ca 2þ stores following activation of G protein-coupled receptors or receptor tyrosine kinases. Over the past two decades, the physiological and pathological relevance of SOCE has been extensively studied. Recently, accumulating evidence suggests associations of altered SOCE with diabetic complications. This review focuses on the implication of SOCE as it pertains to various complications resulting from diabetes. We summarize recent findings by us and others on the involvement of abnormal SOCE in the development of diabetic complications, such as diabetic nephropathy and diabetic vasculopathy. The underlying mechanisms that mediate the diabetes-associated alterations of SOCE are also discussed. The SOCE pathway may be considered as a potential therapeutic target for diabetes-associated diseases.

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STIM1 Restores Coronary Endothelial Function in Type 1 Diabetic Mice

Cited by 55 publications

References 50 publications

Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation

Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation

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

Store-operated calcium entry and diabetic complications

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