Functional role of phosphodiesterase 3 in cardiomyocyte apoptosis: implication in heart failure.
BACKGROUND
Myocyte apoptosis plays an important role in pathological cardiac remodeling and the progression of heart failure. cAMP signaling is crucial in the regulation of myocyte apoptosis and cardiac remodeling. Multiple cAMP-hydrolyzing phosphodiesterases (PDEs), such as PDE3 and PDE4, coexist in cardiomyocytes and elicit differential temporal/spatial regulation of cAMP signaling. However, the role of PDE3 and PDE4 in the regulation of cardiomyocyte apoptosis remains unclear. Although chronic treatment with PDE3 inhibitors increases mortality in patients with heart failure, the contribution of PDE3 expression/activity in heart failure is not well known.


RESULTS
In this study we report that PDE3A expression and activity were significantly reduced in human failing hearts as well as mouse hearts with chronic pressure overload. In primary cultured cardiomyocytes, chronic inhibition of PDE3 but not PDE4 activity by pharmacological agents or adenovirus-delivered antisense PDE3A promoted cardiomyocyte apoptosis. Both angiotensin II (Ang II) and the beta-adrenergic receptor agonist isoproterenol selectively induced a sustained downregulation of PDE3A expression and induced cardiomyocyte apoptosis. Restoring PDE3A via adenovirus-delivered expression of wild-type PDE3A1 completely blocked Ang II- and isoproterenol-induced cardiomyocyte apoptosis, suggesting the critical role of PDE3A reduction in cardiomyocyte apoptosis. Moreover, we defined a crucial role for inducible cAMP early repressor expression in PDE3A reduction-mediated cardiomyocyte apoptosis.


CONCLUSIONS
Our results suggest that PDE3A reduction and consequent inducible cAMP early repressor induction are critical events in Ang II- and isoproterenol-induced cardiomyocyte apoptosis and may contribute to the development of heart failure. Drugs that maintain PDE3A function may represent an attractive therapeutic approach to treat heart failure.
Ding
Bo
B
Center for Cardiovascular Research, University of Rochester School of Medicine and Dentistry, Aab Institute of Biomedical Science, Rochester, NY (B.D., J.A., H.W., Q.H., B.C. Berk, C.Y.); Case Western Reserve University, Cleveland, Ohio (R.A.W.); University of Medicine and Dentistry of New Jersey, Newark (C.A.M., J.S.); University of Pittsburgh, Pittsburgh, Pa (A.Z.); and Center for Cellular and Molecular Cardiology, University of Rochester, Rochester, NY (B.C. Blaxall).
Abe
Jun-Ichi
JI
Center for Cardiovascular Research, University of Rochester School of Medicine and Dentistry, Aab Institute of Biomedical Science, Rochester, NY (B.D., J.A., H.W., Q.H., B.C. Berk, C.Y.); Case Western Reserve University, Cleveland, Ohio (R.A.W.); University of Medicine and Dentistry of New Jersey, Newark (C.A.M., J.S.); University of Pittsburgh, Pittsburgh, Pa (A.Z.); and Center for Cellular and Molecular Cardiology, University of Rochester, Rochester, NY (B.C. Blaxall).
Wei
Heng
H
Center for Cardiovascular Research, University of Rochester School of Medicine and Dentistry, Aab Institute of Biomedical Science, Rochester, NY (B.D., J.A., H.W., Q.H., B.C. Berk, C.Y.); Case Western Reserve University, Cleveland, Ohio (R.A.W.); University of Medicine and Dentistry of New Jersey, Newark (C.A.M., J.S.); University of Pittsburgh, Pittsburgh, Pa (A.Z.); and Center for Cellular and Molecular Cardiology, University of Rochester, Rochester, NY (B.C. Blaxall).
Huang
Qunhua
Q
Center for Cardiovascular Research, University of Rochester School of Medicine and Dentistry, Aab Institute of Biomedical Science, Rochester, NY (B.D., J.A., H.W., Q.H., B.C. Berk, C.Y.); Case Western Reserve University, Cleveland, Ohio (R.A.W.); University of Medicine and Dentistry of New Jersey, Newark (C.A.M., J.S.); University of Pittsburgh, Pittsburgh, Pa (A.Z.); and Center for Cellular and Molecular Cardiology, University of Rochester, Rochester, NY (B.C. Blaxall).
Walsh
Richard A
RA
Center for Cardiovascular Research, University of Rochester School of Medicine and Dentistry, Aab Institute of Biomedical Science, Rochester, NY (B.D., J.A., H.W., Q.H., B.C. Berk, C.Y.); Case Western Reserve University, Cleveland, Ohio (R.A.W.); University of Medicine and Dentistry of New Jersey, Newark (C.A.M., J.S.); University of Pittsburgh, Pittsburgh, Pa (A.Z.); and Center for Cellular and Molecular Cardiology, University of Rochester, Rochester, NY (B.C. Blaxall).
Molina
Carlos A
CA
Center for Cardiovascular Research, University of Rochester School of Medicine and Dentistry, Aab Institute of Biomedical Science, Rochester, NY (B.D., J.A., H.W., Q.H., B.C. Berk, C.Y.); Case Western Reserve University, Cleveland, Ohio (R.A.W.); University of Medicine and Dentistry of New Jersey, Newark (C.A.M., J.S.); University of Pittsburgh, Pittsburgh, Pa (A.Z.); and Center for Cellular and Molecular Cardiology, University of Rochester, Rochester, NY (B.C. Blaxall).
Zhao
Allan
A
Center for Cardiovascular Research, University of Rochester School of Medicine and Dentistry, Aab Institute of Biomedical Science, Rochester, NY (B.D., J.A., H.W., Q.H., B.C. Berk, C.Y.); Case Western Reserve University, Cleveland, Ohio (R.A.W.); University of Medicine and Dentistry of New Jersey, Newark (C.A.M., J.S.); University of Pittsburgh, Pittsburgh, Pa (A.Z.); and Center for Cellular and Molecular Cardiology, University of Rochester, Rochester, NY (B.C. Blaxall).
Sadoshima
Junichi
J
Center for Cardiovascular Research, University of Rochester School of Medicine and Dentistry, Aab Institute of Biomedical Science, Rochester, NY (B.D., J.A., H.W., Q.H., B.C. Berk, C.Y.); Case Western Reserve University, Cleveland, Ohio (R.A.W.); University of Medicine and Dentistry of New Jersey, Newark (C.A.M., J.S.); University of Pittsburgh, Pittsburgh, Pa (A.Z.); and Center for Cellular and Molecular Cardiology, University of Rochester, Rochester, NY (B.C. Blaxall).
Blaxall
Burns C
BC
Center for Cardiovascular Research, University of Rochester School of Medicine and Dentistry, Aab Institute of Biomedical Science, Rochester, NY (B.D., J.A., H.W., Q.H., B.C. Berk, C.Y.); Case Western Reserve University, Cleveland, Ohio (R.A.W.); University of Medicine and Dentistry of New Jersey, Newark (C.A.M., J.S.); University of Pittsburgh, Pittsburgh, Pa (A.Z.); and Center for Cellular and Molecular Cardiology, University of Rochester, Rochester, NY (B.C. Blaxall).
Berk
Bradford C
BC
Center for Cardiovascular Research, University of Rochester School of Medicine and Dentistry, Aab Institute of Biomedical Science, Rochester, NY (B.D., J.A., H.W., Q.H., B.C. Berk, C.Y.); Case Western Reserve University, Cleveland, Ohio (R.A.W.); University of Medicine and Dentistry of New Jersey, Newark (C.A.M., J.S.); University of Pittsburgh, Pittsburgh, Pa (A.Z.); and Center for Cellular and Molecular Cardiology, University of Rochester, Rochester, NY (B.C. Blaxall).
Yan
Chen
C
Center for Cardiovascular Research, University of Rochester School of Medicine and Dentistry, Aab Institute of Biomedical Science, Rochester, NY (B.D., J.A., H.W., Q.H., B.C. Berk, C.Y.); Case Western Reserve University, Cleveland, Ohio (R.A.W.); University of Medicine and Dentistry of New Jersey, Newark (C.A.M., J.S.); University of Pittsburgh, Pittsburgh, Pa (A.Z.); and Center for Cellular and Molecular Cardiology, University of Rochester, Rochester, NY (B.C. Blaxall).
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D016022:Case-Control Studies; D000242:Cyclic AMP / Q000096:biosynthesis; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006333:Heart Failure / Q000188:drug therapy / Q000473:pathology*; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D032383:Myocytes, Cardiac / Q000473:pathology*
D004791:Enzyme Inhibitors; D000804:Angiotensin II; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517287:PDE3A protein, human; C517289:Pde3a protein, mouse; D007545:Isoproterenol