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Inhibition of serine/threonine protein phosphatase PP1 protects cardiomyocytes from tunicamycin-induced apoptosis and I/R through the upregulation of p-eIF2α

The serine/threonine protein phosphatase PP1 mediates the dephosphorylation of phosphorylated eukaryotic translation initiation factor 2 subunit α (p-eIF2α), which is a central regulator of protein synthesis. In the present study, we examined the protective effects of PP1–12 (an inhibitor of the ser...

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Autores principales: LIU, CHUN-LEI, HE, YUN-YUN, LI, XIN, LI, RUI-JUN, HE, KUN-LUN, WANG, LI-LI
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3926518/
https://www.ncbi.nlm.nih.gov/pubmed/24366244
http://dx.doi.org/10.3892/ijmm.2013.1603
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author LIU, CHUN-LEI
HE, YUN-YUN
LI, XIN
LI, RUI-JUN
HE, KUN-LUN
WANG, LI-LI
author_facet LIU, CHUN-LEI
HE, YUN-YUN
LI, XIN
LI, RUI-JUN
HE, KUN-LUN
WANG, LI-LI
author_sort LIU, CHUN-LEI
collection PubMed
description The serine/threonine protein phosphatase PP1 mediates the dephosphorylation of phosphorylated eukaryotic translation initiation factor 2 subunit α (p-eIF2α), which is a central regulator of protein synthesis. In the present study, we examined the protective effects of PP1–12 (an inhibitor of the serine/threonine protein phosphatase PP1) against tunicamycin (TM)-induced apoptosis in cultured cardiomyocytes in vitro, as well as in an in vivo model of ischemia/reperfusion (I/R) injury in rat hearts. Neonatal cardiomyocytes cultured from the ventricles of the hearts of 1-day-old Wistar rats were exposed to various concentrations of PP1–12 (0.3, 1 and 3 μmol/l) for 30 min, followed by treatment with TM for 36 h. Cell viability was assessed by adenosine triphosphate (ATP) bioluminescence, and the results revealed that pre-treatment with PP1–12 protected cell viability. Western blot analysis revealed that PP1–12 induced eIF2α phosphorylation and immuncytochemistry indicated that PP1–12 downregulated the expression of C/EBP homologous protein (CHOP), which is related to apoptosis. PP1–12 suppressed cell apoptosis, with maximum protective effects displayed at the concentration of 3 μmol/l. For the in vivo experiments, male Sprague-Dawley rats were randomly divided into 5 groups: i) sham-operated; ii) vehicle (I/R + DMSO); iii) I/R + 1 mg/kg/day PP1–12; iv) I/R + 3 mg/kg/day PP1–12; and v) I/R + 10 mg/kg/day PP1–12. PP1–12 reduced the expression of cleaved caspase-12 and increased the phosphorylation of eIF2α, as revealed by western blot analysis. By calculating the apoptotic index (AI), we found that 10 mg/kg/day PP1–12 exerted the most pronounced anti-apoptotic effect. The infarction area was significantly decreased following treatment with this concentration of PP1–12, as revealed by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Taken together, these data suggest that PP1–12 protects cardiomyocytes from TM- and I/R-induced apoptosis, and this effect is achieved at least in part through the inhibition of cell apoptosis and the induction of eIF2α phosphorylation.
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spelling pubmed-39265182014-02-24 Inhibition of serine/threonine protein phosphatase PP1 protects cardiomyocytes from tunicamycin-induced apoptosis and I/R through the upregulation of p-eIF2α LIU, CHUN-LEI HE, YUN-YUN LI, XIN LI, RUI-JUN HE, KUN-LUN WANG, LI-LI Int J Mol Med Articles The serine/threonine protein phosphatase PP1 mediates the dephosphorylation of phosphorylated eukaryotic translation initiation factor 2 subunit α (p-eIF2α), which is a central regulator of protein synthesis. In the present study, we examined the protective effects of PP1–12 (an inhibitor of the serine/threonine protein phosphatase PP1) against tunicamycin (TM)-induced apoptosis in cultured cardiomyocytes in vitro, as well as in an in vivo model of ischemia/reperfusion (I/R) injury in rat hearts. Neonatal cardiomyocytes cultured from the ventricles of the hearts of 1-day-old Wistar rats were exposed to various concentrations of PP1–12 (0.3, 1 and 3 μmol/l) for 30 min, followed by treatment with TM for 36 h. Cell viability was assessed by adenosine triphosphate (ATP) bioluminescence, and the results revealed that pre-treatment with PP1–12 protected cell viability. Western blot analysis revealed that PP1–12 induced eIF2α phosphorylation and immuncytochemistry indicated that PP1–12 downregulated the expression of C/EBP homologous protein (CHOP), which is related to apoptosis. PP1–12 suppressed cell apoptosis, with maximum protective effects displayed at the concentration of 3 μmol/l. For the in vivo experiments, male Sprague-Dawley rats were randomly divided into 5 groups: i) sham-operated; ii) vehicle (I/R + DMSO); iii) I/R + 1 mg/kg/day PP1–12; iv) I/R + 3 mg/kg/day PP1–12; and v) I/R + 10 mg/kg/day PP1–12. PP1–12 reduced the expression of cleaved caspase-12 and increased the phosphorylation of eIF2α, as revealed by western blot analysis. By calculating the apoptotic index (AI), we found that 10 mg/kg/day PP1–12 exerted the most pronounced anti-apoptotic effect. The infarction area was significantly decreased following treatment with this concentration of PP1–12, as revealed by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Taken together, these data suggest that PP1–12 protects cardiomyocytes from TM- and I/R-induced apoptosis, and this effect is achieved at least in part through the inhibition of cell apoptosis and the induction of eIF2α phosphorylation. D.A. Spandidos 2014-03 2013-12-23 /pmc/articles/PMC3926518/ /pubmed/24366244 http://dx.doi.org/10.3892/ijmm.2013.1603 Text en Copyright © 2014, Spandidos Publications http://creativecommons.org/licenses/by/3.0 This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.
spellingShingle Articles
LIU, CHUN-LEI
HE, YUN-YUN
LI, XIN
LI, RUI-JUN
HE, KUN-LUN
WANG, LI-LI
Inhibition of serine/threonine protein phosphatase PP1 protects cardiomyocytes from tunicamycin-induced apoptosis and I/R through the upregulation of p-eIF2α
title Inhibition of serine/threonine protein phosphatase PP1 protects cardiomyocytes from tunicamycin-induced apoptosis and I/R through the upregulation of p-eIF2α
title_full Inhibition of serine/threonine protein phosphatase PP1 protects cardiomyocytes from tunicamycin-induced apoptosis and I/R through the upregulation of p-eIF2α
title_fullStr Inhibition of serine/threonine protein phosphatase PP1 protects cardiomyocytes from tunicamycin-induced apoptosis and I/R through the upregulation of p-eIF2α
title_full_unstemmed Inhibition of serine/threonine protein phosphatase PP1 protects cardiomyocytes from tunicamycin-induced apoptosis and I/R through the upregulation of p-eIF2α
title_short Inhibition of serine/threonine protein phosphatase PP1 protects cardiomyocytes from tunicamycin-induced apoptosis and I/R through the upregulation of p-eIF2α
title_sort inhibition of serine/threonine protein phosphatase pp1 protects cardiomyocytes from tunicamycin-induced apoptosis and i/r through the upregulation of p-eif2α
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3926518/
https://www.ncbi.nlm.nih.gov/pubmed/24366244
http://dx.doi.org/10.3892/ijmm.2013.1603
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