Role of Ca2+/calmodulin-stimulated cyclic nucleotide phosphodiesterase 1 in mediating cardiomyocyte hypertrophy.
BACKGROUND
Cyclic nucleotide phosphodiesterases (PDEs) through the degradation of cGMP play critical roles in maintaining cardiomyocyte homeostasis. Ca(2+)/calmodulin (CaM)-activated cGMP-hydrolyzing PDE1 family may play a pivotal role in balancing intracellular Ca(2+)/CaM and cGMP signaling; however, its function in cardiomyocytes is unknown.


OBJECTIVE
Herein, we investigate the role of Ca(2+)/CaM-stimulated PDE1 in regulating pathological cardiomyocyte hypertrophy in neonatal and adult rat ventricular myocytes and in the heart in vivo.


RESULTS
Inhibition of PDE1 activity using a PDE1-selective inhibitor, IC86340, or downregulation of PDE1A using siRNA prevented phenylephrine induced pathological myocyte hypertrophy and hypertrophic marker expression in neonatal and adult rat ventricular myocytes. Importantly, administration of the PDE1 inhibitor IC86340 attenuated cardiac hypertrophy induced by chronic isoproterenol infusion in vivo. Both PDE1A and PDE1C mRNA and protein were detected in human hearts; however, PDE1A expression was conserved in rodent hearts. Moreover, PDE1A expression was significantly upregulated in vivo in the heart and myocytes from various pathological hypertrophy animal models and in vitro in isolated neonatal and adult rat ventricular myocytes treated with neurohumoral stimuli such as angiotensin II (Ang II) and isoproterenol. Furthermore, PDE1A plays a critical role in phenylephrine-induced reduction of intracellular cGMP- and cGMP-dependent protein kinase (PKG) activity and thereby cardiomyocyte hypertrophy in vitro.


CONCLUSIONS
These results elucidate a novel role for Ca(2+)/CaM-stimulated PDE1, particularly PDE1A, in regulating pathological cardiomyocyte hypertrophy via a cGMP/PKG-dependent mechanism, thereby demonstrating Ca(2+) and cGMP signaling cross-talk during cardiac hypertrophy.
Miller
Clint L
CL
Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, NY 14642, USA.
Oikawa
Masayoshi
M
Cai
Yujun
Y
Wojtovich
Andrew P
AP
Nagel
David J
DJ
Xu
Xiangbin
X
Xu
Haodong
H
Florio
Vince
V
Rybalkin
Sergei D
SD
Beavo
Joseph A
JA
Chen
Yiu-Fai
YF
Li
Jian-Dong
JD
Blaxall
Burns C
BC
Abe
Jun-ichi
J
Yan
Chen
C
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000528:radiation effects*; D002147:Calmodulin / Q000378:metabolism*; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology*; D002316:Cardiotonic Agents / Q000009:adverse effects / Q000494:pharmacology; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles / Q000201:enzymology; D006801:Humans; D007545:Isoproterenol / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology*
D002147:Calmodulin; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D000804:Angiotensin II; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; C527988:Pde1A protein, mouse; C517263:Pde1a protein, rat; D006152:Cyclic GMP; D007545:Isoproterenol; D002118:Calcium