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Activation of Extracellular Signal-Regulated Kinase 5 Reduces Cardiac Apoptosis and Dysfunction via Inhibition of a Phosphodiesterase 3A/Inducible cAMP Early Repressor Feedback Loop
| Content Provider | Scilit |
|---|---|
| Author | Yan, Chen Ding, Bo Shishido, Tetsuro Woo, Chang-Hoon Itoh, Seigo Jeon, Kye-Im Liu, Weimin Xu, Haodong McClain, Carolyn Molina, Carlos A. Blaxall, Burns C. Abe, Jun-Ichi |
| Copyright Year | 2007 |
| Description | Journal: Circulation Research 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. |
| Related Links | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115673/pdf https://www.ahajournals.org/doi/reader/10.1161/01.RES.0000259045.49371.9c |
| Ending Page | 519 |
| Page Count | 10 |
| Starting Page | 510 |
| ISSN | 00097330 |
| e-ISSN | 15244571 |
| DOI | 10.1161/01.res.0000259045.49371.9c |
| Journal | Circulation Research |
| Issue Number | 4 |
| Volume Number | 100 |
| Language | English |
| Publisher | Ovid Technologies (Wolters Kluwer Health) |
| Publisher Date | 2007-03-02 |
| Access Restriction | Open |
| Subject Keyword | Journal: Circulation Research Peripheral Vascular Disease Phosphodiesterase 3 Inducible Camp Early Repressor Heart Failure Insulin-like Growth Factor-1 |
| Content Type | Text |
| Resource Type | Article |
| Subject | Physiology Cardiology and Cardiovascular Medicine |
