title: Activation of extracellular signal-regulated kinase 5 reduces cardiac apoptosis and dysfunction via inhibition of a phosphodiesterase 3A/inducible cAMP early repressor feedback loop.
abstract: 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.
authors.affiliation: Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. Chen_Yan@urmc.rochester.edu
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
authors.forename: Bo
authors.initials: B
authors.lastname: Ding
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Shishido
authors.forename: Chang-Hoon
authors.initials: CH
authors.lastname: Woo
authors.forename: Seigo
authors.initials: S
authors.lastname: Itoh
authors.forename: Kye-Im
authors.initials: KI
authors.lastname: Jeon
authors.forename: Weimin
authors.initials: W
authors.lastname: Liu
authors.forename: Haodong
authors.initials: H
authors.lastname: Xu
authors.forename: Carolyn
authors.initials: C
authors.lastname: McClain
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Molina
authors.forename: Burns C
authors.initials: BC
authors.lastname: Blaxall
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Abe
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001794:Blood Pressure / Q000235:genetics; D051786:Cyclic AMP Response Element Modulator / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D004317:Doxorubicin / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D004789:Enzyme Activation / Q000235:genetics; D025461:Feedback, Physiological / Q000502:physiology*; D006333:Heart Failure / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D051381:Rats
chemical_list: D051786:Cyclic AMP Response Element Modulator; D004317:Doxorubicin; D048054:Mitogen-Activated Protein Kinase 7; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517289:Pde3a protein, mouse; C517290:Pde3a protein, rat