Andrea M Isidori1, Marisa Cornacchione2, Federica Barbagallo1, Antonio Di Grazia3, Florencia Barrios3, Lorenzo Fassina4, Lucia Monaco5, Elisa Giannetta1, Daniele Gianfrilli1, Silvio Garofalo2, Xiaoxiao Zhang6, Xiongwen Chen6, Yang K Xiang7, Andrea Lenzi1, Manuela Pellegrini2, Fabio Naro8. 1. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy. 2. Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy. 3. Department of Anatomical, Histological, Forensic, and Orthopaedic Sciences, Sapienza University, Rome, Italy. 4. Department of Industrial and Information Engineering, University of Pavia, Pavia, Italy. 5. Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy. 6. Department of Physiology, Temple University, Philadelphia, PA, USA. 7. Department of Pharmacology, University of California, Davis, CA, USA. 8. Department of Anatomical, Histological, Forensic, and Orthopaedic Sciences, Sapienza University, Rome, Italy fabio.naro@uniroma1.it.
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 β2AR, but not β1AR 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. Published on behalf of the European Society of Cardiology. All rights reserved.
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 β2AR, but not β1AR 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. Published on behalf of the European Society of Cardiology. All rights reserved.
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