Editors' ChoiceHeart Failure

A change of heart for phosphodiesterase signaling

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Science Translational Medicine  01 Apr 2015:
Vol. 7, Issue 281, pp. 281ec52
DOI: 10.1126/scitranslmed.aaa8316

Heart failure is a leading cause of death and disability worldwide, highlighting an urgent need for novel pharmacotherapies. The drug sildenafil, which increases cellular cyclic guanosine monophosphate (cGMP) levels by blocking an enzyme phosphodiesterase type 5A (PDE5A) that chews it up, has been shown to be beneficial in animal models of heart failure. However, the limited efficacy of sildenafil in human heart failure trials, particularly in patients with preserved left ventricular systolic function, has led scientists to search for new ways to activate cGMP signaling in the failing heart.

Lee et al. now identify PDE9A as a new cGMP-degrading enzyme in cardiomyocytes that may be a promising drug target. The authors showed that PDE9A is active in failing rodent and human hearts. Pharmacologic inhibition or genetic silencing of PDE9A was protective in pressure-overload mediated cardiac hypertrophy and heart failure in mice. In contrast to myocardial PDE5A activity, which is coupled to nitric oxide (NO)–dependent cGMP production, PDE9A-mediated effects on cGMP were shown to be coupled to atrial natriuretic peptide (ANP) signaling and were NO-independent. NO independence is advantageous for a new drug in the stressed heart, as endogenous NO bioactivity is often depressed in human cardiovascular disease.

This study identifies PDE9A inhibition as a new therapeutic strategy to increase cGMP in the failing heart. In addition to pursuing further preclinical testing of PDE9A inhibitors, gaining a deeper insight into the precise molecular basis by which the ANP receptor specifically couples to PDE9A may elucidate additional therapeutic targets in heart disease.

D. I. Lee et al., Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease. Nature 519, 472–476 (2015). [Full]

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