Abstract
Previous studies by our group have demonstrated that the calcium imbalance in rat hepatic stellate cells (HSCs) can induce endoplasmic reticulum stress (ERS) and promote cell apoptosis. KN-62, an inhibitor of Calmodulin kinase II (CaMK II), can decrease the expression of CaMK II that plays a major role in regulating the steady state of intracellular Ca2+. Uridine triphosphate (UTP) plays a biological role in increasing indirectly the level of intracellular Ca2+. In the experiment, we demonstrate that KN-62 and UTP can inhibit the proliferation and promote the apoptosis in HSCs, increase the level of intracellular Ca2+ and the expression of ERS protein GRP78, and increase the apoptosis protein Caspase-12 and Bax expression, while decrease the expression of Bcl-2 protein. Our findings indicate that the CaMK II/Ca2+ signaling pathway regulates the ERS apoptosis pathway and induces HSC apoptosis.
Keywords:
Apoptosis; CaMK II inhibitor KN-62; Endoplasmic reticulum stress; Hepatic fibrosis; Hepatic stellate cells; Uridine triphosphate.
Copyright © 2021 Elsevier B.V. All rights reserved.
MeSH terms
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
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Apoptosis / drug effects
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Apoptosis / genetics
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Calcium / metabolism*
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / antagonists & inhibitors*
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
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Caspase 12 / genetics
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Caspase 12 / metabolism
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Cations, Divalent
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Cell Line
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Endoplasmic Reticulum Chaperone BiP
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Endoplasmic Reticulum Stress / drug effects*
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Endoplasmic Reticulum Stress / genetics
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism
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Hepatic Stellate Cells / cytology
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Hepatic Stellate Cells / drug effects*
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Hepatic Stellate Cells / metabolism
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Humans
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Signal Transduction
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Transforming Growth Factor beta1 / pharmacology*
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Uridine Triphosphate / metabolism
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Uridine Triphosphate / pharmacology*
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bcl-2-Associated X Protein / genetics
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bcl-2-Associated X Protein / metabolism
Substances
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BAX protein, human
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Cations, Divalent
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Endoplasmic Reticulum Chaperone BiP
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Enzyme Inhibitors
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HSPA5 protein, human
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Heat-Shock Proteins
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TGFB1 protein, human
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Transforming Growth Factor beta1
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bcl-2-Associated X Protein
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KN 62
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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CASP12 protein, human
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Caspase 12
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Calcium
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Uridine Triphosphate