STIM1 Regulates Endothelial Calcium Overload and Cytokine Upregulation During Sepsis

Qiu, Xiaochen; Dong, Kaisheng; Sun, Ruoyan

doi:10.1016/j.jss.2020.12.016

Cited by 10 publications

(4 citation statements)

References 23 publications

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“…Further uncertainty for a STIM-independent effect of SARAF on Orai1 function arises from studies in HEK293 cells which showed that SARAF fails to reach ER-PM sites in the absence of STIM1 [52] and that the deletion of both STIM1 and STIM2 is sufficient to fully block Ca 2+ entry [87] despite significant levels of endogenous SARAF and Orai1 proteins in these cells [52,63]. Finally, reduced levels of either Orai1, SARAF, or STIM1 attenuate Ca 2+ entry in endothelial cells, suggesting that all three components affect SOCE in these cells [88,89]. The bi-directional effect of SARAF on CRAC channel activation and inactivation is highly intriguing and suggests a broader role for SARAF in the regulation of SOCE.…”

Section: Current Models For Scdi By Sarafmentioning

confidence: 99%

“…These findings therefore suggest that in the heart, STIM1 and SARAF undergo a cooperative but not antagonizing interaction. The positive contribution of SARAF, STIM1, and Orai1 to both store-operated Ca 2+ entry in endothelial cells and to angiogenesis [77,88,89,125] suggests that such a cooperative relationship between SARAF and CRAC channels may also occur in additional cell types and tissues.…”

Section: The Role Of Saraf In Pathologies Of Cardiovascular Tissuesmentioning

confidence: 99%

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Regulation of Store-Operated Ca2+ Entry by SARAF

Dagan

Palty

2021

Cells

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Calcium (Ca2+) signaling plays a dichotomous role in cellular biology, controlling cell survival and proliferation on the one hand and cellular toxicity and cell death on the other. Store-operated Ca2+ entry (SOCE) by CRAC channels represents a major pathway for Ca2+ entry in non-excitable cells. The CRAC channel has two key components, the endoplasmic reticulum Ca2+ sensor stromal interaction molecule (STIM) and the plasma-membrane Ca2+ channel Orai. Physical coupling between STIM and Orai opens the CRAC channel and the resulting Ca2+ flux is regulated by a negative feedback mechanism of slow Ca2+ dependent inactivation (SCDI). The identification of the SOCE-associated regulatory factor (SARAF) and investigations of its role in SCDI have led to new functional and molecular insights into how SOCE is controlled. In this review, we provide an overview of the functional and molecular mechanisms underlying SCDI and discuss how the interaction between SARAF, STIM1, and Orai1 shapes Ca2+ signaling in cells.

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Section: Current Models For Scdi By Sarafmentioning

confidence: 99%

Section: The Role Of Saraf In Pathologies Of Cardiovascular Tissuesmentioning

confidence: 99%

Regulation of Store-Operated Ca2+ Entry by SARAF

Dagan

Palty

2021

Cells

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“…Among them, the cAMP/PKA pathway forms calcium signals in various cell types including cardiomyocytes and neurons [47,48]. Calcium ion channels are involved in the occurrence and development of sepsis [49]; calcium overload is the main mechanism of systemic inflammatory response and endothelial cell injury in sepsis [50]. e accumulation of Ca2+ is an important cause of the progression from sepsis to multiple organ dysfunction [51].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Mechanism and Key Active Ingredients of Shenfu Injection in Sepsis: A Network Pharmacology and Molecular Docking Approach

Yuan

Yang

Huang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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At present, although the early treatment of sepsis is advocated, the treatment effect of sepsis is unsatisfactory, and the mortality rate remains high. Shenfu injection (SFI) has been used to treat sepsis with good clinical efficacy. Based on network pharmacology, this study adopted a new research strategy to identify the potential therapeutic targets and key active ingredients of SFI for sepsis from the perspective of the pathophysiology of sepsis. This analysis identified 28 active ingredients of SFI based on UHPLC-QQQ MS, including 18 ginsenosides and 10 aconite alkaloids. 59 targets were associated with the glycocalyx and sepsis pathways. Based on the number of targets related to the pathophysiological process of sepsis, we identified songorine, ginsenoside Rf, ginsenoside Re, and karacoline as the key active ingredients of SFI for the treatment of sepsis. According to the cluster analysis of MCODE and the validation on the GEO dataset, LGALS3, BCHE, AKT1, and IL2 were identified as the core targets. This study further explored the therapeutic mechanism and the key active ingredients of SFI in sepsis and provided candidate compounds for drug development.

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“…Recent studies have suggested that STIM1 plays an important role in regulating endothelial barrier function [110]. The septic serum or LPS could stimulate SOCE in human umbilical vein ECs, RNAi-mediated knockdown of STIM1 greatly inhibited LPS-induced inflammatory cytokine expression [111][112][113]. Moreover, in case of endotoxemia, SOCCs function got impaired, which led to decreased activation of Orai1 and further disrupted intracellular Ca 2+ homeostasis, ultimately triggering vascular hyporesponsiveness [114].…”

Section: Store-operated Calcium Channels (Soccs)mentioning

confidence: 99%

Ion Channels Remodeling in the Regulation of Vascular Hyporesponsiveness During Shock

Li,

Chen

et al. 2024

Microcirculation

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Shock is characterized with vascular hyporesponsiveness to vasoconstrictors, thereby to cause refractory hypotension, insufficient tissue perfusion, and multiple organ dysfunction. The vascular hyporeactivity persisted even though norepinephrine and fluid resuscitation were administrated, it is of critical importance to find new potential target. Ion channels are crucial in the regulation of cell membrane potential and affect vasoconstriction and vasodilation. It has been demonstrated that many types of ion channels including K+ channels, Ca2+ permeable channels, and Na+ channels exist in vascular smooth muscle cells and endothelial cells, contributing to the regulation of vascular homeostasis and vasomotor function. An increasing number of studies suggested that the structural and functional alterations of ion channels located in arteries contribute to vascular hyporesponsiveness during shock, but the underlying mechanisms remained to be fully clarified. Therefore, the expression and functional changes in ion channels in arteries associated with shock are reviewed, to pave the way for further exploring the potential of ion channel‐targeted compounds in treating refractory hypotension in shock.

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STIM1 Regulates Endothelial Calcium Overload and Cytokine Upregulation During Sepsis

Cited by 10 publications

References 23 publications

Regulation of Store-Operated Ca2+ Entry by SARAF

Regulation of Store-Operated Ca2+ Entry by SARAF

Therapeutic Mechanism and Key Active Ingredients of Shenfu Injection in Sepsis: A Network Pharmacology and Molecular Docking Approach

Ion Channels Remodeling in the Regulation of Vascular Hyporesponsiveness During Shock

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