Activation of Extracellular Signal-Regulated Kinase 5 Reduces Cardiac Apoptosis and Dysfunction via Inhibition of a Phosphodiesterase 3A/Inducible cAMP Early Repressor Feedback Loop
| Autor: | Tetsuro Shishido, Seigo Itoh, Bo Ding, Weimin Liu, Haodong Xu, Kye-Im Jeon, Jun Ichi Abe, Carlos A. Molina, Burns C. Blaxall, Chen Yan, Chang Hoon Woo, Carolyn McClain |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
MAPK/ERK pathway
Mef2 Programmed cell death medicine.medical_specialty CAMP-Responsive Element Modulator Physiology Phosphodiesterase 3 Apoptosis Blood Pressure Mice Transgenic Biology Article Cyclic AMP Response Element Modulator Mice Downregulation and upregulation Internal medicine medicine Animals Myocytes Cardiac Protein kinase A education Mitogen-Activated Protein Kinase 7 health care economics and organizations Feedback Physiological Heart Failure Pressure overload education.field_of_study Cyclic Nucleotide Phosphodiesterases Type 3 Rats Cell biology Enzyme Activation Endocrinology 3' 5'-Cyclic-AMP Phosphodiesterases Doxorubicin Cardiology and Cardiovascular Medicine |
| Zdroj: | Circulation Research. 100:510-519 |
| ISSN: | 1524-4571 0009-7330 |
| Popis: | Substantial evidence suggests that the progressive loss of cardiomyocytes caused by apoptosis significantly contributes to the development of heart failure. beta-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 5alpha (MEK5alpha) (CA-MEK5alpha-Tg). In wild-type mice, pressure overload- or doxorubicin-induced significant reduction of PDE3A expression and subsequent ICER induction. Cardiac specific expression of CA-MEK5alpha 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|