title: Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease.
abstract: Cyclic guanosine monophosphate (cGMP) is a second messenger molecule that transduces nitric-oxide- and natriuretic-peptide-coupled signalling, stimulating phosphorylation changes by protein kinase G. Enhancing cGMP synthesis or blocking its degradation by phosphodiesterase type 5A (PDE5A) protects against cardiovascular disease. However, cGMP stimulation alone is limited by counter-adaptions including PDE upregulation. Furthermore, although PDE5A regulates nitric-oxide-generated cGMP, nitric oxide signalling is often depressed by heart disease. PDEs controlling natriuretic-peptide-coupled cGMP remain uncertain. Here we show that cGMP-selective PDE9A (refs 7, 8) is expressed in the mammalian heart, including humans, and is upregulated by hypertrophy and cardiac failure. PDE9A regulates natriuretic-peptide- rather than nitric-oxide-stimulated cGMP in heart myocytes and muscle, and its genetic or selective pharmacological inhibition protects against pathological responses to neurohormones, and sustained pressure-overload stress. PDE9A inhibition reverses pre-established heart disease independent of nitric oxide synthase (NOS) activity, whereas PDE5A inhibition requires active NOS. Transcription factor activation and phosphoproteome analyses of myocytes with each PDE selectively inhibited reveals substantial differential targeting, with phosphorylation changes from PDE5A inhibition being more sensitive to NOS activation. Thus, unlike PDE5A, PDE9A can regulate cGMP signalling independent of the nitric oxide pathway, and its role in stress-induced heart disease suggests potential as a therapeutic target.
authors: Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
authors: Dong I
authors: DI
authors: Lee
authors: Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
authors: Guangshuo
authors: G
authors: Zhu
authors: Advanced Medical Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Kanagawa 227-0033, Japan.
authors: Takashi
authors: T
authors: Sasaki
authors: Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
authors: Gun-Sik
authors: GS
authors: Cho
authors: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors: Nazha
authors: N
authors: Hamdani
authors: 1] Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA [2] Heart Institute and Advanced Clinical Biosystems Research Institute, Cedar Sinai Medical Center, 8700 Beverly Blvd, AHSP A9229 Los Angeles, California 90048, USA.
authors: Ronald
authors: R
authors: Holewinski
authors: Department of Physiology, Institute of Bioscience and Biotechnology, BK21 plus Graduate Program, Kangwon National University College of Medicine, Chuncheon 200-701, Korea.
authors: Su-Hyun
authors: SH
authors: Jo
authors: Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
authors: Thomas
authors: T
authors: Danner
authors: Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
authors: Manling
authors: M
authors: Zhang
authors: Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
authors: Peter P
authors: PP
authors: Rainer
authors: Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
authors: Djahida
authors: D
authors: Bedja
authors: Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
authors: Jonathan A
authors: JA
authors: Kirk
authors: Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
authors: Mark J
authors: MJ
authors: Ranek
authors: Department of Pharmacology, University of Vermont, Burlington, Vermont 05405, USA.
authors: Wolfgang R
authors: WR
authors: Dostmann
authors: Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
authors: Chulan
authors: C
authors: Kwon
authors: Department of Medicine, Division of Cardiovascular Medicine, Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors: Kenneth B
authors: KB
authors: Margulies
authors: 1] Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA [2] Heart Institute and Advanced Clinical Biosystems Research Institute, Cedar Sinai Medical Center, 8700 Beverly Blvd, AHSP A9229 Los Angeles, California 90048, USA.
authors: Jennifer E
authors: JE
authors: Van Eyk
authors: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors: Walter J
authors: WJ
authors: Paulus
authors: Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
authors: Eiki
authors: E
authors: Takimoto
authors: Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
authors: David A
authors: DA
authors: Kass
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001024:Aortic Valve Stenosis / Q000150:complications; D006332:Cardiomegaly / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032342:Muscle Cells / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology; D045265:Natriuretic Peptides / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011312:Pressure; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological; D015854:Up-Regulation
chemical_list: D045265:Natriuretic Peptides; D010726:Phosphodiesterase Inhibitors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C116137:PDE9A protein, human; C507055:Pde9a protein, mouse; D006152:Cyclic GMP