Published online before print February 1, 2007, doi: 10.1161/01.RES.0000259045.49371.9c
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Submitted on August 7, 2006
Revised on January 11, 2007
Accepted on January 18, 2007
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 *;
From the Cardiovascular Research Institute (C.Y., B.D., T.S., C.-H.W., S.I., K.-I.J., W.L., C.M., B.C.B., J.-i.A.), University of Rochester, NY; Department of Pathology and Laboratory Medicine (H.X.), University of Rochester, NY; and University of Medicine and Dentistry of New Jersey (C.A.M.), Newark.
* To whom correspondence should be addressed. E-mail: Chen_Yan{at}urmc.rochester.edu.
Substantial evidence suggests that the progressive loss of cardiomyocytes caused by apoptosis significantly contributes to the development of heart failure. 
-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 kinase/ERK5
(MEK5) (CA-MEK5-Tg). In wild-type mice, pressure overload- or doxorubicin-induced significant reduction of PDE3A expression and subsequent ICER induction. Cardiac specific expression of CA-MEK5 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.
Key words: ERK5 • phosphodiesterase 3 • inducible cAMP early repressor • heart failure • insulin-like growth factor-1
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