Activation of Extracellular Signal-Regulated Kinase 5 Reduces Cardiac Apoptosis and Dysfunction via Inhibition of a Phosphodiesterase 3A/Inducible cAMP Early Repressor Feedback Loop

Authors

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

Document Type

Preprint

Publication Date

3-1-2007

Journal / Book Title

Circulation research

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.

DOI

10.1161/01.RES.0000259045.49371.9c

Montclair State University Digital Commons Citation

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.; and 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" (2007). Department of Biology Faculty Scholarship and Creative Works. 266.
https://digitalcommons.montclair.edu/biology-facpubs/266

Rights

NIH Public Access Author Manuscript; available in PMC 2014 July 30. Published in final edited form as: Circ Res. 2007 March 2; 100(4): 510–519. doi:10.1161/01.RES.0000259045.49371.9c.