Journal Article

Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease

Takimoto, Eiki, Rainer, Peter P., Paulus, Walter J., Cho, Gun-Sik, Ranek, Mark J., Dostmann, Wolfgang R., Lee, Dong I., Bedja, Djahida, Kwon, Chulan, Margulies, Kenneth B., Zhang, Manling, Kirk, Jonathan A., Kass, David A., Zhu, Guangshuo, Sasaki, Takashi, Jo, Su-Hyun, Danner, Thomas, Hamdani, Nazha, Holewinski, Ronald, Van Eyk, Jennifer E.

2015

Overview

The inhibition, in mice, of the phosphodiesterase PDE9A, which specifically regulates natriuretic-peptide-coupled cGMP signalling, is independent of nitric oxide and is upregulated in failing human hearts, and can reverse pre-established stress-induced heart disease. A new treatment for heart disease Work in animals has shown that inhibition of phosphodiesterase type 5A (PDE5A) with, for example, Viagra, can protect the heart from pathological stress by preventing the degradation of nitric-oxide-generated cGMP. However, nitric oxide signalling is often depressed in cardiovascular disease, potentially explaining the disappointing results of PDE5A inhibition in clinical trials. David Kass and colleagues now identify an alternative target, PDE9A, which specifically regulates natriuretic-peptide-coupled cGMP signalling, and is independent of nitric oxide. They show that PDE9A is upregulated in failing human hearts and that its inhibition in mice can reverse pre-established stress-induced heart disease. PDE9A inhibitors seem to be well tolerated in humans and are being investigated in clinical trials for neurocognitive disease. The new results suggest that these inhibitors may also find an application in heart disease. 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 1 , 2 . However, cGMP stimulation alone is limited by counter-adaptions including PDE upregulation 3 . Furthermore, although PDE5A regulates nitric-oxide-generated cGMP 4 , 5 , nitric oxide signalling is often depressed by heart disease 6 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/109 / 13/51 / 13/89 / 13/95 / 14 / 14/1 / 14/19 / 14/34 / 14/63 / 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors / 3',5'-Cyclic-AMP Phosphodiesterases - deficiency / 3',5'-Cyclic-AMP Phosphodiesterases - genetics / 3',5'-Cyclic-AMP Phosphodiesterases - metabolism / 38 / 38/32 / 59 / 631/443/592/1540 / 631/80/304 / 64 / 64/60 / 692/699/75/230 / 96 / Animals / Aortic Valve Stenosis - complications / Cardiomegaly - drug therapy / Cardiomegaly - enzymology / Cardiomegaly - etiology / Cardiomegaly - metabolism / Cardiovascular disease / Cardiovascular diseases / Cyclic GMP - metabolism / Cyclic guanylic acid / Genes / Health aspects / Heart enlargement / Heart failure / Humanities and Social Sciences / Humans / Kinases / letter / Male / Mice / Mice, Inbred C57BL / multidisciplinary / Muscle Cells - enzymology / Myocardium - enzymology / Natriuretic Peptides - metabolism / Nitric oxide / Nitric Oxide - metabolism / Nitric Oxide Synthase / Peptides / Phosphodiesterase Inhibitors - pharmacology / Phosphodiesterase Inhibitors - therapeutic use / Phosphodiesterases / Physiological aspects / Pressure / Protein expression / Proteins / Rodents / Science / Signal Transduction - drug effects / Stress, Physiological / Up-Regulation