A positive feedback loop of phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis.
cAMP plays crucial roles in cardiac remodeling and the progression of heart failure. Recently, we found that expression of cAMP hydrolyzing phosphodiesterase 3A (PDE3A) was significantly reduced in human failing hearts, accompanied by up-regulation of inducible cAMP early repressor (ICER) expression. Angiotensin II (Ang II) and the beta-adrenergic receptor agonist isoproterenol (ISO) also induced persistent PDE3A down-regulation and concomitant ICER up-regulation in vitro, which is important in Ang II- and ISO-induced cardiomyocyte apoptosis. We hypothesized that interactions between PDE3A and ICER may constitute an autoregulatory positive feedback loop (PDE3A-ICER feedback loop), and this loop would cause persistent PDE3A down-regulation and ICER up-regulation. Here, we demonstrate that ICER induction repressed PDE3A gene transcription. PDE3A down-regulation activated cAMP/PKA signaling, leading to ICER up-regulation via PKA-dependent stabilization of ICER. With respect to Ang II, the initiation of the PDE3A-ICER feedback loop depends on activation of Ang II type 1 receptor (AT1R), classical PKC(s), and CREB (cAMP response element binding protein). We further show that the PDE3A-ICER feedback loop is essential for Ang II-induced cardiomyocyte apoptosis. ISO and PDE3 inhibitors also induced the PDE3A-ICER feedback loop and subsequent cardiomyocyte apoptosis, highlighting the importance of this PDE3A-ICER feedback loop and cAMP signaling in cardiomyocyte apoptosis. Our findings may provide a therapeutic paradigm to prevent cardiomyocyte apoptosis and the progression of heart failure by inhibiting the PDE3A-ICER feedback loop.
Ding
Bo
B
Cardiovascular Research Institute, Department of Pathology, University of Rochester, Rochester, NY 14642, USA.
Abe
Jun-Ichi
J
Wei
Heng
H
Xu
Haodong
H
Che
Wenyi
W
Aizawa
Toru
T
Liu
Weimin
W
Molina
Carlos A
CA
Sadoshima
Junichi
J
Blaxall
Burns C
BC
Berk
Bradford C
BC
Yan
Chen
C
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001794:Blood Pressure; D017124:Conserved Sequence / Q000235:genetics; D051786:Cyclic AMP Response Element Modulator / Q000378:metabolism*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D025461:Feedback, Physiological / Q000502:physiology; D005786:Gene Expression Regulation; D023281:Genomics; D006339:Heart Rate; D008156:Luciferases; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology
D051786:Cyclic AMP Response Element Modulator; D008156:Luciferases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517287:PDE3A protein, human; C517290:Pde3a protein, rat