Stanniocalcin 1 Prevents Cytosolic Ca2+ Overload and Cell Hypercontracture in Cardiomyocytes

Koizumi, Keiichi; Hoshiai, Minako; Ishida, Hideyuki; Ohyama, Kenji; Sugiyama, Hisashi; Naito, Akira; Toda, Takako; Nakazawa, Hiroe; Nakazawa, Shinpei

doi:10.1253/circj.71.796

Cited by 23 publications

(15 citation statements)

References 26 publications

(27 reference statements)

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“…The mammalian STC1 homolog shares sequence homology with its fish counterpart, and has been implicated in a multitude of cellular processes, including ischemic injury, apoptosis, angiogenesis, inflammation, cancer biology, bone and muscle development, cellular metabolism, calcium regulation, differentiation and endothelial permeability [4, 9, 12, 17, 18, 20, 30, 33, 38-40, 42, 44, 45]. Numerous reports have shown a role for STC1 as a mediator of apoptosis [20, 22, 42], demonstrating both pro-apoptotic and anti-apoptotic roles depending upon cell type and stimulus.…”

Section: Discussionmentioning

confidence: 99%

Stanniocalcin1 is a key mediator of amyloidogenic light chain induced cardiotoxicity

et al. 2013

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Immunoglobulin light chain (LC) amyloidosis (AL) results from overproduction of circulating amyloidogenic LC proteins and subsequent amyloid fibril deposition in organs. Mortality in AL amyloidosis patients is highly associated with a rapidly progressive AL cardiomyopathy, marked by profound impairment of diastolic and systolic cardiac function and significant early mortality. While myocardial fibril deposition contributes to the severe diastolic dysfunction seen in AL cardiomyopathy patients, the degree of fibril deposition has not been found to correlate with prognosis. Previously, we and others showed a direct cardiotoxic effect of amyloidogenic LC proteins (AL-LC), which may contribute to the pathophysiology and mortality observed in AL cardiomyopathy patients. However, the mechanisms underlying AL-LC related cardiotoxicity remain unknown. Mammalian stanniocalcin1 (STC1) is associated with a number of cellular processes including oxidative stress and cell death. Herein, we find that STC1 expression is elevated in cardiac tissue from AL cardiomyopathy patients, and is induced in isolated cardiomyocytes in response to AL-LC, but not non-amyloidogenic LC. STC1 overexpression in vitro recapitulates the pathophysiology of AL-LC mediated cardiotoxicity, with increased ROS production, contractile dysfunction and cell death. Overexpression of STC1 in vivo results in significant cardiac dysfunction and cell death. Genetic silencing of STC1 prevents AL-LC induced cardiotoxicity in cardiomyocytes and protects against AL-LC induced cell death and early mortality in zebrafish. The cardiotoxic effects of STC1 appears to be mediated via mitochondrial dysfunction as indicated by loss of mitochondrial membrane potential, ROS production and increased mitochondrial calcium levels. Collectively, this work identifies STC1 as a critical determinant of AL-LC cardiotoxicity.

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Section: Discussionmentioning

confidence: 99%

Stanniocalcin1 is a key mediator of amyloidogenic light chain induced cardiotoxicity

et al. 2013

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“…Because rapid [Ca 2+ ]i transient occurs in these cells, slow kinase reactions such as MLCK are not suitable as a [Ca 2+ ]i sensor. 5 Troponin directly binds to actin and structural change in troponin causes the release of troponin I, which inhibits the ATPase activity of myosin. Using this non-enzyme signal, increased [Ca 2+ ]i rapidly changes the contractility of these muscles.…”

Section: [Ca 2+ ]I Increase and Muscle Contractionmentioning

confidence: 99%

Phosphorylation of Myosin Regulatory Light Chain by Myosin Light Chain Kinase, and Muscle Contraction

Takashima

2009

Circ J

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Not only muscle contraction, but also most cell movements depend on myosin -actin interaction using ATP. Many components of the contraction machinery are involved in the efficient coupling of energy source and force development. Among these, I have focused on myosin light chain kinase (MLCK) in this review. MLCK phosphorylates myosin regulatory light chain and controls all 3 types of muscle contraction: skeletal muscle, smooth muscle, and cardiac muscle. However, each muscle has specific MLCK and the role of MLCK in each muscle is different. This difference explains the specific role of each muscle in vivo and contributes to the activity of various force development in different ways in each tissue. Therefore, I also review the differences in the connection between each MLCK and muscle contraction in the 3 muscle types. (Circ J 2009; 73: 208 -213)

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“…It is possible that STC1 may mediate its effects through its putative role in calcium regulation. STC1 has been shown to be capable of regulating intracellular calcium (Sheikh-Hamad et al, 2000;Kanellis et al, 2003;Koizumi et al, 2007), and the activation of pathways that govern cellular proliferation and death, such as the protein kinase C (PKC) pathway, rely heavily upon intracellular calcium signaling. The PKC pathway is of particular interest because it can promote MEK and ERK1/2 activation (Bai et al, 2002) and has also been shown to regulate STC1 expression (Yeung et al, 2003).…”

Section: Regulation Of Oxidative Stress Response By Stc1mentioning

confidence: 99%

Stanniocalcin-1 acts in a negative feedback loop in the prosurvival ERK1/2 signaling pathway during oxidative stress

2009

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Mammalian Stanniocalcin-1 (STC1) is a glycoprotein that has been implicated in various biological processes including angiogenesis. Aberrant STC1 expression has been reported in breast, ovarian and prostate cancers, but the significance of this is not well understood. Here, we report that oxidative stress caused a 40-fold increase in STC1 levels in mouse embryo fibroblasts (MEFs). STC1À/À MEFs were resistant to growth inhibition and cell death induced by H 2 O 2 or by 20% O 2 (which is hyperoxic for most mammalian cells); this is the first phenotype reported for STC1-null cells. STC1À/À cells had higher levels of activated MEK and ERK1/2 than their wild-type (WT) counterparts, and these levels were all reduced by stable expression of exogenous STC1 in STC1À/À cells. Furthermore, pharmacological inhibition by PD98059 or UO126 of MEK and therefore of ERK1/2 activation restored sensitivity of STC1À/À cells to oxidative stress. We also found that H 2 O 2 -induced STC1 expression in WT cells was abolished by inhibition of ERK1/2 activation. Thus, the ERK1/2 signaling pathway upregulates STC1 expression, which in turn downregulates the level of activated MEK and consequently ERK1/2 in a novel negative feedback loop. Therefore, STC1 expression downregulates prosurvival ERK1/2 signaling and reduces survival under conditions of oxidative stress.

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Stanniocalcin 1 Prevents Cytosolic Ca2+ Overload and Cell Hypercontracture in Cardiomyocytes

Cited by 23 publications

References 26 publications

Stanniocalcin1 is a key mediator of amyloidogenic light chain induced cardiotoxicity

Stanniocalcin1 is a key mediator of amyloidogenic light chain induced cardiotoxicity

Phosphorylation of Myosin Regulatory Light Chain by Myosin Light Chain Kinase, and Muscle Contraction

Stanniocalcin-1 acts in a negative feedback loop in the prosurvival ERK1/2 signaling pathway during oxidative stress

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