Publication Date:
2015-03-25
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376609/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376609/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Dong I -- Zhu, Guangshuo -- Sasaki, Takashi -- Cho, Gun-Sik -- Hamdani, Nazha -- Holewinski, Ronald -- Jo, Su-Hyun -- Danner, Thomas -- Zhang, Manling -- Rainer, Peter P -- Bedja, Djahida -- Kirk, Jonathan A -- Ranek, Mark J -- Dostmann, Wolfgang R -- Kwon, Chulan -- Margulies, Kenneth B -- Van Eyk, Jennifer E -- Paulus, Walter J -- Takimoto, Eiki -- Kass, David A -- HHSN268201000032C/HL/NHLBI NIH HHS/ -- HL-07227/HL/NHLBI NIH HHS/ -- HL-089297/HL/NHLBI NIH HHS/ -- HL-093432/HL/NHLBI NIH HHS/ -- HL-119012/HL/NHLBI NIH HHS/ -- HL089847/HL/NHLBI NIH HHS/ -- HL105993/HL/NHLBI NIH HHS/ -- HL68891/HL/NHLBI NIH HHS/ -- N01HV28180/HL/NHLBI NIH HHS/ -- P01 HL107153/HL/NHLBI NIH HHS/ -- R01 HL089297/HL/NHLBI NIH HHS/ -- R01 HL089847/HL/NHLBI NIH HHS/ -- R01 HL093432/HL/NHLBI NIH HHS/ -- R01 HL105993/HL/NHLBI NIH HHS/ -- R01 HL111198/HL/NHLBI NIH HHS/ -- R01 HL119012/HL/NHLBI NIH HHS/ -- T32 HL007227/HL/NHLBI NIH HHS/ -- England -- Nature. 2015 Mar 26;519(7544):472-6. doi: 10.1038/nature14332. Epub 2015 Mar 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA. ; Advanced Medical Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Kanagawa 227-0033, Japan. ; Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. ; 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. ; Department of Physiology, Institute of Bioscience and Biotechnology, BK21 plus Graduate Program, Kangwon National University College of Medicine, Chuncheon 200-701, Korea. ; Department of Pharmacology, University of Vermont, Burlington, Vermont 05405, USA. ; Department of Medicine, Division of Cardiovascular Medicine, Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25799991" target="_blank"〉PubMed〈/a〉
Keywords:
3',5'-Cyclic-AMP Phosphodiesterases/antagonists &
;
inhibitors/deficiency/genetics/*metabolism
;
Animals
;
Aortic Valve Stenosis/complications
;
Cardiomegaly/drug therapy/*enzymology/etiology/*metabolism
;
Cyclic GMP/*metabolism
;
Humans
;
Male
;
Mice
;
Mice, Inbred C57BL
;
Muscle Cells/enzymology
;
Myocardium/enzymology
;
Natriuretic Peptides/metabolism
;
*Nitric Oxide/metabolism
;
Nitric Oxide Synthase
;
Phosphodiesterase Inhibitors/pharmacology/therapeutic use
;
Pressure
;
Signal Transduction/drug effects
;
Stress, Physiological
;
Up-Regulation
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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