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(Circulation Research. 2007;100:510.)
© 2007 American Heart Association, Inc.

Molecular Medicine

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 A. Molina, Burns C. Blaxall, Jun-ichi Abe

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 Department of Biochemistry and Molecular Biology University of Medicine and Dentistry of New Jersey (C.A.M.), Newark.

Correspondence to Chen Yan, PhD, and Jun-ichi Abe, MD, PhD, Cardiovascular Research Institute, Box 679, 601 Elmwood Ave, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642. E-mail Chen_Yan{at}urmc.rochester.edu and Jun-ichi_abe@urmc.rochester.edu

Substantial evidence suggests that the progressive loss of cardiomyocytes caused by apoptosis significantly contributes to the development of heart failure. ß-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 5 (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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