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(Circulation Research. 2009;105:956.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Role of Ca²⁺/Calmodulin-Stimulated Cyclic Nucleotide Phosphodiesterase 1 in Mediating Cardiomyocyte Hypertrophy

Clint L. Miller, Masayoshi Oikawa, Yujun Cai, Andrew P. Wojtovich, David J. Nagel, Xiangbin Xu, Haodong Xu, Vince Florio, Sergei D. Rybalkin, Joseph A. Beavo, Yiu-Fai Chen, Jian-Dong Li, Burns C. Blaxall, Jun-ichi Abe, Chen Yan

From the Department of Pharmacology and Physiology (C.L.M., A.P.W., D.J.N.), Medicine (C.L.M., M.O., Y.C., H.X., B.C.B., J.-i.A., C.Y.), Microbiology and Immunology (X.X., J.-D.L.), Pathology and Laboratory Medicine (H.X.) and Aab Cardiovascular Research Institute (C.L.M., M.O., Y.C., H.X., B.C.B., J.-i.A., C.Y.), University of Rochester School of Medicine and Dentistry, NY; Omeros Corporation (V.F.), Seattle, Wash; Department of Pharmacology (S.D.R., J.A.B.), University of Washington, Seattle; and Department of Medicine (Y.-F.C.), University of Alabama, Birmingham.

Correspondence to Chen Yan, PhD, Aab Cardiovascular Research Institute, University of Rochester, 601 Elmwood Ave, Box CVRI, Rochester, NY 14642. E-mail chen_yan{at}urmc.rochester.edu

Rationale: Cyclic nucleotide phosphodiesterases (PDEs) through the degradation of cGMP play critical roles in maintaining cardiomyocyte homeostasis. Ca²⁺/calmodulin (CaM)-activated cGMP-hydrolyzing PDE1 family may play a pivotal role in balancing intracellular Ca²⁺/CaM and cGMP signaling; however, its function in cardiomyocytes is unknown.

Objective: Herein, we investigate the role of Ca²⁺/CaM-stimulated PDE1 in regulating pathological cardiomyocyte hypertrophy in neonatal and adult rat ventricular myocytes and in the heart in vivo.

Methods and 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 Ca²⁺/CaM-stimulated PDE1, particularly PDE1A, in regulating pathological cardiomyocyte hypertrophy via a cGMP/PKG-dependent mechanism, thereby demonstrating Ca²⁺ and cGMP signaling cross-talk during cardiac hypertrophy.

Key Words: phosphodiesterase • cGMP • cardiomyocyte • cardiac hypertrophy

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