Inhibition of type 5 phosphodiesterase counteracts β2-adrenergic signalling in beating cardiomyocytes

Andrea M. Isidori, Marisa Cornacchione, Federica Barbagallo, Antonio Di Grazia, Florencia Barrios, Lorenzo Fassina, Lucia Monaco, Elisa Giannetta, Daniele Gianfrilli, Silvio Garofalo, Xiaoxiao Zhang, Xiongwen Chen, Yang Kevin Xiang, Andrea Lenzi, Manuela Pellegrini, Fabio Naro

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Aims: Compartmentalization of cAMP and PKA activity in cardiac muscle cells plays a key role in maintaining basal and enhanced contractility stimulated by sympathetic nerve activity. In cardiomyocytes, activation of adrenergic receptor increases cAMP production, which is countered by the hydrolytic activity of selective phosphodiesterases (PDEs). The intracellular regional dynamics of cAMP production and hydrolysis modulate downstream signals resulting in different biological responses. The interplay between beta receptors (βARs) signalling and phosphodiesterase 5 (PDE5) activity remains to be addressed. Methods and results: Using combined strategies with pharmacological inhibitors and genetic deletion of PDEs and βAR isoforms, we revealed a specific pool of cAMP that is under dual regulation by PDE2 and, indirectly, PDE5 activity. Inhibition of PDE5 with sildenafil produces a cGMP-dependent activation of PDE2 that attenuates cAMP generation induced by βAR agonists, with concomitant modulation of stimulated contraction rate and calcium transients. PDE2 haploinsufficiency abolished the effects of sildenafil. The negative chronotropic effect of PDE5 inhibition through PDE2 activation was also observed in sinoatrial node tissue from adult mice. PDE5 inhibition selectively lowered contraction rate stimulated by β<inf>2</inf>AR, but not β<inf>1</inf>AR activation, supporting a compartmentalization of the cGMP-modulated pool of cAMP. Conclusion: These data identify a new effect of PDE5 inhibitors on the modulation of cardiomyocyte response to adrenergic stimulation via PDE5-PDE2-mediated cross-talk.

Original languageEnglish (US)
Pages (from-to)408-420
Number of pages13
JournalCardiovascular Research
Volume106
Issue number3
DOIs
StatePublished - Jun 1 2015

Keywords

  • Chronotropy
  • PDE2
  • PDE5
  • Sildenafil
  • βARs

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

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    Isidori, A. M., Cornacchione, M., Barbagallo, F., Di Grazia, A., Barrios, F., Fassina, L., Monaco, L., Giannetta, E., Gianfrilli, D., Garofalo, S., Zhang, X., Chen, X., Xiang, Y. K., Lenzi, A., Pellegrini, M., & Naro, F. (2015). Inhibition of type 5 phosphodiesterase counteracts β2-adrenergic signalling in beating cardiomyocytes. Cardiovascular Research, 106(3), 408-420. https://doi.org/10.1093/cvr/cvv123