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

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

*Corresponding author for this work

Research output: Contribution to journalArticle

140 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)472-476
Number of pages5
JournalNature
Volume519
Issue number7544
DOIs
Publication statusPublished - 26 Mar 2015
Externally publishedYes

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    Lee, D. I., Zhu, G., Sasaki, T., Cho, G. S., Hamdani, N., Holewinski, R., ... Kass, D. A. (2015). Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease. Nature, 519(7544), 472-476. https://doi.org/10.1038/nature14332