Glycoprotein 130 regulates cardiac myocyte survival in doxorubicin-induced apoptosis through phosphatidylinositol 3-kinase/Akt phosphorylation and Bcl-xL/caspase-3 interaction

Shinji Negoro, Hidemasa Oh, Eiroh Tone, Keita Kunisada, Yasushi Fujio, Kenneth Walsh, Tadamitsu Kishimoto, Keiko Yamauchi-Takihara

Research output: Contribution to journalArticle

169 Citations (Scopus)

Abstract

Background - We recently reported that the activation of glycoprotein (gp) 130 by leukemia inhibitory factor (LIF) upregulates Bcl-xL and exerts antiapoptotic effects in cardiac myocytes. In addition, LIF induces activation of phosphatidylinositol (PI) 3-kinase and Akt, which are known to be required for cell survival. However, their regulatory roles in cell death remain unknown. Methods and Results - We investigated the fate of these proteins and the cytoprotective effects of LIF on doxorubicin (DOX)-induced apoptosis in cultured neonatal rat cardiac myocytes. Myocyte apoptosis increased significantly in DOX-treated cells but was significantly reduced by LIF pretreatment. The kinase activities of PI 3-kinase and Akt declined below basal levels but were partially recovered with LIF. Moreover, DOX-induced caspase-3 activation and decrease in Bcl-xL abundance are completely inhibited by LIF and caspase inhibitor. LIF phosphorylates Bad through PI 3-kinase and reduces the heterodimerization of Bad with Bcl-xL. Adenovirus transfer of the constitutively active form of Akt to cardiac myocytes restored cardiac myocyte survival after DOX treatment. Conversely, the dominant-negative form of Akt inhibited LIF-induced increase in cell viability and suppression of caspase-9 activation. Conclusions - Activation of gp130 inhibits DOX-induced cell death in cardiac myocytes, resulting in the restoration of PI 3-kinase/Akt activities and in the inactivation of caspase-3, leading to facilitation of the protective function of Bcl-xL.

Original languageEnglish
Pages (from-to)555-561
Number of pages7
JournalCirculation
Volume103
Issue number4
Publication statusPublished - Jan 30 2001
Externally publishedYes

Fingerprint

Phosphatidylinositol 3-Kinase
Leukemia Inhibitory Factor
Cardiac Myocytes
Caspase 3
Doxorubicin
Glycoproteins
Phosphorylation
Apoptosis
Cell Survival
Cell Death
Caspase Inhibitors
Caspase 9
Adenoviridae
Muscle Cells
Phosphotransferases
Up-Regulation

Keywords

  • Caspases
  • Doxorubicin
  • Glycoproteins
  • Kinases

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Glycoprotein 130 regulates cardiac myocyte survival in doxorubicin-induced apoptosis through phosphatidylinositol 3-kinase/Akt phosphorylation and Bcl-xL/caspase-3 interaction. / Negoro, Shinji; Oh, Hidemasa; Tone, Eiroh; Kunisada, Keita; Fujio, Yasushi; Walsh, Kenneth; Kishimoto, Tadamitsu; Yamauchi-Takihara, Keiko.

In: Circulation, Vol. 103, No. 4, 30.01.2001, p. 555-561.

Research output: Contribution to journalArticle

Negoro, S, Oh, H, Tone, E, Kunisada, K, Fujio, Y, Walsh, K, Kishimoto, T & Yamauchi-Takihara, K 2001, 'Glycoprotein 130 regulates cardiac myocyte survival in doxorubicin-induced apoptosis through phosphatidylinositol 3-kinase/Akt phosphorylation and Bcl-xL/caspase-3 interaction', Circulation, vol. 103, no. 4, pp. 555-561.
Negoro, Shinji ; Oh, Hidemasa ; Tone, Eiroh ; Kunisada, Keita ; Fujio, Yasushi ; Walsh, Kenneth ; Kishimoto, Tadamitsu ; Yamauchi-Takihara, Keiko. / Glycoprotein 130 regulates cardiac myocyte survival in doxorubicin-induced apoptosis through phosphatidylinositol 3-kinase/Akt phosphorylation and Bcl-xL/caspase-3 interaction. In: Circulation. 2001 ; Vol. 103, No. 4. pp. 555-561.
@article{d4a4d8b97b374320bb1a96b02403f95c,
title = "Glycoprotein 130 regulates cardiac myocyte survival in doxorubicin-induced apoptosis through phosphatidylinositol 3-kinase/Akt phosphorylation and Bcl-xL/caspase-3 interaction",
abstract = "Background - We recently reported that the activation of glycoprotein (gp) 130 by leukemia inhibitory factor (LIF) upregulates Bcl-xL and exerts antiapoptotic effects in cardiac myocytes. In addition, LIF induces activation of phosphatidylinositol (PI) 3-kinase and Akt, which are known to be required for cell survival. However, their regulatory roles in cell death remain unknown. Methods and Results - We investigated the fate of these proteins and the cytoprotective effects of LIF on doxorubicin (DOX)-induced apoptosis in cultured neonatal rat cardiac myocytes. Myocyte apoptosis increased significantly in DOX-treated cells but was significantly reduced by LIF pretreatment. The kinase activities of PI 3-kinase and Akt declined below basal levels but were partially recovered with LIF. Moreover, DOX-induced caspase-3 activation and decrease in Bcl-xL abundance are completely inhibited by LIF and caspase inhibitor. LIF phosphorylates Bad through PI 3-kinase and reduces the heterodimerization of Bad with Bcl-xL. Adenovirus transfer of the constitutively active form of Akt to cardiac myocytes restored cardiac myocyte survival after DOX treatment. Conversely, the dominant-negative form of Akt inhibited LIF-induced increase in cell viability and suppression of caspase-9 activation. Conclusions - Activation of gp130 inhibits DOX-induced cell death in cardiac myocytes, resulting in the restoration of PI 3-kinase/Akt activities and in the inactivation of caspase-3, leading to facilitation of the protective function of Bcl-xL.",
keywords = "Caspases, Doxorubicin, Glycoproteins, Kinases",
author = "Shinji Negoro and Hidemasa Oh and Eiroh Tone and Keita Kunisada and Yasushi Fujio and Kenneth Walsh and Tadamitsu Kishimoto and Keiko Yamauchi-Takihara",
year = "2001",
month = "1",
day = "30",
language = "English",
volume = "103",
pages = "555--561",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

TY - JOUR

T1 - Glycoprotein 130 regulates cardiac myocyte survival in doxorubicin-induced apoptosis through phosphatidylinositol 3-kinase/Akt phosphorylation and Bcl-xL/caspase-3 interaction

AU - Negoro, Shinji

AU - Oh, Hidemasa

AU - Tone, Eiroh

AU - Kunisada, Keita

AU - Fujio, Yasushi

AU - Walsh, Kenneth

AU - Kishimoto, Tadamitsu

AU - Yamauchi-Takihara, Keiko

PY - 2001/1/30

Y1 - 2001/1/30

N2 - Background - We recently reported that the activation of glycoprotein (gp) 130 by leukemia inhibitory factor (LIF) upregulates Bcl-xL and exerts antiapoptotic effects in cardiac myocytes. In addition, LIF induces activation of phosphatidylinositol (PI) 3-kinase and Akt, which are known to be required for cell survival. However, their regulatory roles in cell death remain unknown. Methods and Results - We investigated the fate of these proteins and the cytoprotective effects of LIF on doxorubicin (DOX)-induced apoptosis in cultured neonatal rat cardiac myocytes. Myocyte apoptosis increased significantly in DOX-treated cells but was significantly reduced by LIF pretreatment. The kinase activities of PI 3-kinase and Akt declined below basal levels but were partially recovered with LIF. Moreover, DOX-induced caspase-3 activation and decrease in Bcl-xL abundance are completely inhibited by LIF and caspase inhibitor. LIF phosphorylates Bad through PI 3-kinase and reduces the heterodimerization of Bad with Bcl-xL. Adenovirus transfer of the constitutively active form of Akt to cardiac myocytes restored cardiac myocyte survival after DOX treatment. Conversely, the dominant-negative form of Akt inhibited LIF-induced increase in cell viability and suppression of caspase-9 activation. Conclusions - Activation of gp130 inhibits DOX-induced cell death in cardiac myocytes, resulting in the restoration of PI 3-kinase/Akt activities and in the inactivation of caspase-3, leading to facilitation of the protective function of Bcl-xL.

AB - Background - We recently reported that the activation of glycoprotein (gp) 130 by leukemia inhibitory factor (LIF) upregulates Bcl-xL and exerts antiapoptotic effects in cardiac myocytes. In addition, LIF induces activation of phosphatidylinositol (PI) 3-kinase and Akt, which are known to be required for cell survival. However, their regulatory roles in cell death remain unknown. Methods and Results - We investigated the fate of these proteins and the cytoprotective effects of LIF on doxorubicin (DOX)-induced apoptosis in cultured neonatal rat cardiac myocytes. Myocyte apoptosis increased significantly in DOX-treated cells but was significantly reduced by LIF pretreatment. The kinase activities of PI 3-kinase and Akt declined below basal levels but were partially recovered with LIF. Moreover, DOX-induced caspase-3 activation and decrease in Bcl-xL abundance are completely inhibited by LIF and caspase inhibitor. LIF phosphorylates Bad through PI 3-kinase and reduces the heterodimerization of Bad with Bcl-xL. Adenovirus transfer of the constitutively active form of Akt to cardiac myocytes restored cardiac myocyte survival after DOX treatment. Conversely, the dominant-negative form of Akt inhibited LIF-induced increase in cell viability and suppression of caspase-9 activation. Conclusions - Activation of gp130 inhibits DOX-induced cell death in cardiac myocytes, resulting in the restoration of PI 3-kinase/Akt activities and in the inactivation of caspase-3, leading to facilitation of the protective function of Bcl-xL.

KW - Caspases

KW - Doxorubicin

KW - Glycoproteins

KW - Kinases

UR - http://www.scopus.com/inward/record.url?scp=0035970041&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035970041&partnerID=8YFLogxK

M3 - Article

C2 - 11157722

AN - SCOPUS:0035970041

VL - 103

SP - 555

EP - 561

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 4

ER -