Calmodulin kinases II and IV and calcineurin are involved in leukemia inhibitory factor-induced cardiac hypertrophy in rats

Takahiro Kato, Motoaki Sano, Shunichiro Miyoshi, Toshihiko Sato, Daihiko Hakuno, Hideyuki Ishida, Hiroe Kinoshita-Nakazawa, Keiichi Fukuda, Satoshi Ogawa

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Abstract

We recently reported that leukemia inhibitory factor (LIF) enhances Ca2+](i) through an increase in L-type Ca2+ current (I(Ca,L)) in adult cardiomyocytes. The aim of this study was to investigate whether LIF activates Ca2+-dependent signaling molecules, such as calcineurin and calmodulin kinases II and IV (CaMKII and CaMKIV), and, if so, whether these Ca2+-mediated signaling events contribute to LIF-mediated cardiac hypertrophy. We first confirmed that LIF increased I(Ca,L) and [Ca2+](i) in primary cultured rat neonatal cardiomyocytes. Calcineurin, CaMKII, and CaMKIV activities increased at 2 minutes and peaked by 1.6-, 2.2-, and 2.2-fold, respectively, at 15 minutes. Nicardipine or verapamil fully inhibited these activities. Autophosphorylation of CaMKII was also observed to parallel the timing of CaMKII activity, and this phosphorylation was blocked by nicardipine, verapamil, or EGTA. LIF treatment led to a 3-fold increase in nuclear factor of activated T cell-luciferase activity. To confirm that inositol triphosphate (IP3)-induced Ca2+ release from sarcoplasmic reticulum was not involved in this process, IP3 content and phosphorylation of phospholipase Cγ were investigated. LIF did not increase IP3 content or phosphorylate phospholipase Cγ. KN62 (an inhibitor of CaMKII and CaMKIV) attenuated c-fos, brain natriuretic peptide, α-skeletal actin, and atrial natriuretic peptide expression. KN62 suppressed the LIF-induced increase in [3H]phenylalanine uptake and cell size. Cyclosporin A and FK506 slightly attenuated brain natriuretic peptide but did not affect c-fos or atrial natriuretic peptide expression. Cyclosporin A significantly reduced the LIF-induced increase in [3H]phenylalanine uptake. These findings indicated that LIF activated CaMKII, CaMKIV, and calcineurin through an increase in I(Ca,L) and [Ca2+](i) and that CaMKII, CaMKIV, and calcineurin are critically involved in LIF-induced cardiac hypertrophy.

Original languageEnglish
Pages (from-to)937-945
Number of pages9
JournalCirculation Research
Volume87
Issue number10
Publication statusPublished - 2000 Nov 10

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Leukemia Inhibitory Factor
Calcium-Calmodulin-Dependent Protein Kinases
Calcineurin
Cardiomegaly
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Nicardipine
Brain Natriuretic Peptide
Atrial Natriuretic Factor
Type C Phospholipases
Verapamil
Phenylalanine
Cardiac Myocytes
Cyclosporine
Phosphorylation
NFATC Transcription Factors
Egtazic Acid
Sarcoplasmic Reticulum
Tacrolimus
Inositol
Luciferases

Keywords

  • Calcineurin
  • Calcium
  • Calmodulin-dependent kinase
  • Cardiac hypertrophy
  • Leukemia inhibitory factor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Calmodulin kinases II and IV and calcineurin are involved in leukemia inhibitory factor-induced cardiac hypertrophy in rats. / Kato, Takahiro; Sano, Motoaki; Miyoshi, Shunichiro; Sato, Toshihiko; Hakuno, Daihiko; Ishida, Hideyuki; Kinoshita-Nakazawa, Hiroe; Fukuda, Keiichi; Ogawa, Satoshi.

In: Circulation Research, Vol. 87, No. 10, 10.11.2000, p. 937-945.

Research output: Contribution to journalArticle

Kato, T, Sano, M, Miyoshi, S, Sato, T, Hakuno, D, Ishida, H, Kinoshita-Nakazawa, H, Fukuda, K & Ogawa, S 2000, 'Calmodulin kinases II and IV and calcineurin are involved in leukemia inhibitory factor-induced cardiac hypertrophy in rats', Circulation Research, vol. 87, no. 10, pp. 937-945.
Kato, Takahiro ; Sano, Motoaki ; Miyoshi, Shunichiro ; Sato, Toshihiko ; Hakuno, Daihiko ; Ishida, Hideyuki ; Kinoshita-Nakazawa, Hiroe ; Fukuda, Keiichi ; Ogawa, Satoshi. / Calmodulin kinases II and IV and calcineurin are involved in leukemia inhibitory factor-induced cardiac hypertrophy in rats. In: Circulation Research. 2000 ; Vol. 87, No. 10. pp. 937-945.
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AU - Hakuno, Daihiko

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N2 - We recently reported that leukemia inhibitory factor (LIF) enhances Ca2+](i) through an increase in L-type Ca2+ current (I(Ca,L)) in adult cardiomyocytes. The aim of this study was to investigate whether LIF activates Ca2+-dependent signaling molecules, such as calcineurin and calmodulin kinases II and IV (CaMKII and CaMKIV), and, if so, whether these Ca2+-mediated signaling events contribute to LIF-mediated cardiac hypertrophy. We first confirmed that LIF increased I(Ca,L) and [Ca2+](i) in primary cultured rat neonatal cardiomyocytes. Calcineurin, CaMKII, and CaMKIV activities increased at 2 minutes and peaked by 1.6-, 2.2-, and 2.2-fold, respectively, at 15 minutes. Nicardipine or verapamil fully inhibited these activities. Autophosphorylation of CaMKII was also observed to parallel the timing of CaMKII activity, and this phosphorylation was blocked by nicardipine, verapamil, or EGTA. LIF treatment led to a 3-fold increase in nuclear factor of activated T cell-luciferase activity. To confirm that inositol triphosphate (IP3)-induced Ca2+ release from sarcoplasmic reticulum was not involved in this process, IP3 content and phosphorylation of phospholipase Cγ were investigated. LIF did not increase IP3 content or phosphorylate phospholipase Cγ. KN62 (an inhibitor of CaMKII and CaMKIV) attenuated c-fos, brain natriuretic peptide, α-skeletal actin, and atrial natriuretic peptide expression. KN62 suppressed the LIF-induced increase in [3H]phenylalanine uptake and cell size. Cyclosporin A and FK506 slightly attenuated brain natriuretic peptide but did not affect c-fos or atrial natriuretic peptide expression. Cyclosporin A significantly reduced the LIF-induced increase in [3H]phenylalanine uptake. These findings indicated that LIF activated CaMKII, CaMKIV, and calcineurin through an increase in I(Ca,L) and [Ca2+](i) and that CaMKII, CaMKIV, and calcineurin are critically involved in LIF-induced cardiac hypertrophy.

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