Activation of extracellular signal-regulated kinase 5 reduces cardiac apoptosis and dysfunction via inhibition of a phosphodiesterase 3A/inducible cAMP early repressor feedback loop

Chen Yan, Bo Ding, Tetsuro Shishido, Chang Hoon Woo, Seigo Itoh, Kye Im Jeon, Weimin Liu, Haodong Xu, Carolyn McClain, Carlos Molina, Burns C. Blaxall, Jun Ichi Abe

Research output: Contribution to journalArticleResearchpeer-review

42 Citations (Scopus)

Abstract

Substantial evidence suggests that the progressive loss of cardiomyocytes caused by apoptosis significantly contributes to the development of heart failure. β-Adrenergic receptor activation and subsequent persistent phosphodiesterase 3A (PDE3A) downregulation and concomitant inducible cAMP early repressor (ICER) upregulation (PDE3A/ICER feedback loop) has been proposed to play a key role in the pathogenesis of cardiomyocyte apoptosis. In contrast, insulin-like growth factor-1 can activate cell survival pathways, providing protection against cell death and restoring muscle function. In this study, we found that insulin-like growth factor-1 activates extracellular signal-regulated kinase 5 (ERK5) and inhibits PDE3A/ICER feedback loop. Insulin-like growth factor-1 normalized isoproterenol-mediated PDE3A downregulation and ICER upregulation via ERK5/MEF2 activation, and also inhibited isoproterenol-induced myocyte apoptosis. To determine the physiological relevance of ERK5 activation in regulating PDE3A/ICER feedback loop, we investigated the PDE3A/ICER expression and cardiomyocyte apoptosis in transgenic mice with cardiac specific expression of a constitutively active form of mitogen-activated protein (MAP)/extracellular signal-regulated protein kinase (ERK) kinase 5α (MEK5α) (CA-MEK5α-Tg). In wild-type mice, pressure overload- or doxorubicin-induced significant reduction of PDE3A expression and subsequent ICER induction. Cardiac specific expression of CA-MEK5α rescued pressure overload- or doxorubicin-mediated PDE3A downregulation and ICER upregulation and inhibited myocyte apoptosis as well as subsequent cardiac dysfunction in vivo. These data suggest that preventing the feedback loop of PDE3A/ICER by ERK5 activation could inhibit progression of myocyte apoptosis as well as cardiac dysfunction. These data suggest a new therapeutic paradigm for end stage of heart failure by inhibiting the PDE3A/ICER feedback loop via activating ERK5.

Original languageEnglish
Pages (from-to)510-519
Number of pages10
JournalCirculation Research
Volume100
Issue number4
DOIs
StatePublished - 1 Mar 2007

Fingerprint

Mitogen-Activated Protein Kinase 7
Type 3 Cyclic Nucleotide Phosphodiesterases
Apoptosis
Somatomedins
Cardiac Myocytes
Muscle Cells
Up-Regulation
Down-Regulation
Isoproterenol
Doxorubicin
Heart Failure
Pressure
Extracellular Signal-Regulated MAP Kinases
Mitogens
Adrenergic Receptors
Protein Kinases
Transgenic Mice

Keywords

  • ERK5
  • Heart failure
  • Inducible cAMP early repressor
  • Insulin-like growth factor-1
  • Phosphodiesterase 3

Cite this

Yan, Chen ; Ding, Bo ; Shishido, Tetsuro ; Woo, Chang Hoon ; Itoh, Seigo ; Jeon, Kye Im ; Liu, Weimin ; Xu, Haodong ; McClain, Carolyn ; Molina, Carlos ; Blaxall, Burns C. ; Abe, Jun Ichi. / Activation of extracellular signal-regulated kinase 5 reduces cardiac apoptosis and dysfunction via inhibition of a phosphodiesterase 3A/inducible cAMP early repressor feedback loop. In: Circulation Research. 2007 ; Vol. 100, No. 4. pp. 510-519.
@article{3ecca8d2b1bc42c5a3d6d39003738924,
title = "Activation of extracellular signal-regulated kinase 5 reduces cardiac apoptosis and dysfunction via inhibition of a phosphodiesterase 3A/inducible cAMP early repressor feedback loop",
abstract = "Substantial evidence suggests that the progressive loss of cardiomyocytes caused by apoptosis significantly contributes to the development of heart failure. β-Adrenergic receptor activation and subsequent persistent phosphodiesterase 3A (PDE3A) downregulation and concomitant inducible cAMP early repressor (ICER) upregulation (PDE3A/ICER feedback loop) has been proposed to play a key role in the pathogenesis of cardiomyocyte apoptosis. In contrast, insulin-like growth factor-1 can activate cell survival pathways, providing protection against cell death and restoring muscle function. In this study, we found that insulin-like growth factor-1 activates extracellular signal-regulated kinase 5 (ERK5) and inhibits PDE3A/ICER feedback loop. Insulin-like growth factor-1 normalized isoproterenol-mediated PDE3A downregulation and ICER upregulation via ERK5/MEF2 activation, and also inhibited isoproterenol-induced myocyte apoptosis. To determine the physiological relevance of ERK5 activation in regulating PDE3A/ICER feedback loop, we investigated the PDE3A/ICER expression and cardiomyocyte apoptosis in transgenic mice with cardiac specific expression of a constitutively active form of mitogen-activated protein (MAP)/extracellular signal-regulated protein kinase (ERK) kinase 5α (MEK5α) (CA-MEK5α-Tg). In wild-type mice, pressure overload- or doxorubicin-induced significant reduction of PDE3A expression and subsequent ICER induction. Cardiac specific expression of CA-MEK5α rescued pressure overload- or doxorubicin-mediated PDE3A downregulation and ICER upregulation and inhibited myocyte apoptosis as well as subsequent cardiac dysfunction in vivo. These data suggest that preventing the feedback loop of PDE3A/ICER by ERK5 activation could inhibit progression of myocyte apoptosis as well as cardiac dysfunction. These data suggest a new therapeutic paradigm for end stage of heart failure by inhibiting the PDE3A/ICER feedback loop via activating ERK5.",
keywords = "ERK5, Heart failure, Inducible cAMP early repressor, Insulin-like growth factor-1, Phosphodiesterase 3",
author = "Chen Yan and Bo Ding and Tetsuro Shishido and Woo, {Chang Hoon} and Seigo Itoh and Jeon, {Kye Im} and Weimin Liu and Haodong Xu and Carolyn McClain and Carlos Molina and Blaxall, {Burns C.} and Abe, {Jun Ichi}",
year = "2007",
month = "3",
day = "1",
doi = "10.1161/01.RES.0000259045.49371.9c",
language = "English",
volume = "100",
pages = "510--519",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins Ltd.",
number = "4",

}

Activation of extracellular signal-regulated kinase 5 reduces cardiac apoptosis and dysfunction via inhibition of a phosphodiesterase 3A/inducible cAMP early repressor feedback loop. / Yan, Chen; Ding, Bo; Shishido, Tetsuro; Woo, Chang Hoon; Itoh, Seigo; Jeon, Kye Im; Liu, Weimin; Xu, Haodong; McClain, Carolyn; Molina, Carlos; Blaxall, Burns C.; Abe, Jun Ichi.

In: Circulation Research, Vol. 100, No. 4, 01.03.2007, p. 510-519.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Activation of extracellular signal-regulated kinase 5 reduces cardiac apoptosis and dysfunction via inhibition of a phosphodiesterase 3A/inducible cAMP early repressor feedback loop

AU - Yan, Chen

AU - Ding, Bo

AU - Shishido, Tetsuro

AU - Woo, Chang Hoon

AU - Itoh, Seigo

AU - Jeon, Kye Im

AU - Liu, Weimin

AU - Xu, Haodong

AU - McClain, Carolyn

AU - Molina, Carlos

AU - Blaxall, Burns C.

AU - Abe, Jun Ichi

PY - 2007/3/1

Y1 - 2007/3/1

N2 - Substantial evidence suggests that the progressive loss of cardiomyocytes caused by apoptosis significantly contributes to the development of heart failure. β-Adrenergic receptor activation and subsequent persistent phosphodiesterase 3A (PDE3A) downregulation and concomitant inducible cAMP early repressor (ICER) upregulation (PDE3A/ICER feedback loop) has been proposed to play a key role in the pathogenesis of cardiomyocyte apoptosis. In contrast, insulin-like growth factor-1 can activate cell survival pathways, providing protection against cell death and restoring muscle function. In this study, we found that insulin-like growth factor-1 activates extracellular signal-regulated kinase 5 (ERK5) and inhibits PDE3A/ICER feedback loop. Insulin-like growth factor-1 normalized isoproterenol-mediated PDE3A downregulation and ICER upregulation via ERK5/MEF2 activation, and also inhibited isoproterenol-induced myocyte apoptosis. To determine the physiological relevance of ERK5 activation in regulating PDE3A/ICER feedback loop, we investigated the PDE3A/ICER expression and cardiomyocyte apoptosis in transgenic mice with cardiac specific expression of a constitutively active form of mitogen-activated protein (MAP)/extracellular signal-regulated protein kinase (ERK) kinase 5α (MEK5α) (CA-MEK5α-Tg). In wild-type mice, pressure overload- or doxorubicin-induced significant reduction of PDE3A expression and subsequent ICER induction. Cardiac specific expression of CA-MEK5α rescued pressure overload- or doxorubicin-mediated PDE3A downregulation and ICER upregulation and inhibited myocyte apoptosis as well as subsequent cardiac dysfunction in vivo. These data suggest that preventing the feedback loop of PDE3A/ICER by ERK5 activation could inhibit progression of myocyte apoptosis as well as cardiac dysfunction. These data suggest a new therapeutic paradigm for end stage of heart failure by inhibiting the PDE3A/ICER feedback loop via activating ERK5.

AB - Substantial evidence suggests that the progressive loss of cardiomyocytes caused by apoptosis significantly contributes to the development of heart failure. β-Adrenergic receptor activation and subsequent persistent phosphodiesterase 3A (PDE3A) downregulation and concomitant inducible cAMP early repressor (ICER) upregulation (PDE3A/ICER feedback loop) has been proposed to play a key role in the pathogenesis of cardiomyocyte apoptosis. In contrast, insulin-like growth factor-1 can activate cell survival pathways, providing protection against cell death and restoring muscle function. In this study, we found that insulin-like growth factor-1 activates extracellular signal-regulated kinase 5 (ERK5) and inhibits PDE3A/ICER feedback loop. Insulin-like growth factor-1 normalized isoproterenol-mediated PDE3A downregulation and ICER upregulation via ERK5/MEF2 activation, and also inhibited isoproterenol-induced myocyte apoptosis. To determine the physiological relevance of ERK5 activation in regulating PDE3A/ICER feedback loop, we investigated the PDE3A/ICER expression and cardiomyocyte apoptosis in transgenic mice with cardiac specific expression of a constitutively active form of mitogen-activated protein (MAP)/extracellular signal-regulated protein kinase (ERK) kinase 5α (MEK5α) (CA-MEK5α-Tg). In wild-type mice, pressure overload- or doxorubicin-induced significant reduction of PDE3A expression and subsequent ICER induction. Cardiac specific expression of CA-MEK5α rescued pressure overload- or doxorubicin-mediated PDE3A downregulation and ICER upregulation and inhibited myocyte apoptosis as well as subsequent cardiac dysfunction in vivo. These data suggest that preventing the feedback loop of PDE3A/ICER by ERK5 activation could inhibit progression of myocyte apoptosis as well as cardiac dysfunction. These data suggest a new therapeutic paradigm for end stage of heart failure by inhibiting the PDE3A/ICER feedback loop via activating ERK5.

KW - ERK5

KW - Heart failure

KW - Inducible cAMP early repressor

KW - Insulin-like growth factor-1

KW - Phosphodiesterase 3

UR - http://www.scopus.com/inward/record.url?scp=33947534858&partnerID=8YFLogxK

U2 - 10.1161/01.RES.0000259045.49371.9c

DO - 10.1161/01.RES.0000259045.49371.9c

M3 - Article

VL - 100

SP - 510

EP - 519

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 4

ER -