The role of PDE2 in cardiac hypertrophy

Zoccarato, Anna (2012) The role of PDE2 in cardiac hypertrophy. PhD thesis, University of Glasgow.

Abstract

Cardiomyocytes respond to mechanical and neurohormonal stress with hypertrophic growth. Although in its early stages cardiac hypertrophy is considered as an adaptive response, prolonged hypertrophy is associated with a significant increase in the risk of progression to heart failure, one of the leading causes of death in the Western World today.
3’, 5’- cyclic adenosine monophosphate (cAMP) is an ubiquitous second messenger that is generated by adenylyl cyclases (ACs) upon the stimulation of a G-protein-coupled receptor (GPCR) and degraded by phosphodiesterases (PDEs). The main effector of cAMP is protein kinase A (PKA). In the heart, compartmentalized cAMP/PKA signals play a key role in the regulation of normal cardiac functions and alteration of this signalling pathway have been involved in the pathophysiology of cardiac hypertrophy. PDEs are the sole route to “switch off” cAMP signals and therefore are fundamental regulators of the amplitude and kinetics of cyclic nucleotide responses, of their location of the dynamics of signal propagation.
In this study, I set up an in vitro model of cardiac hypertrophy in primary cultured neonatal rat cardiac myocytes and I investigated the role of PDEs in modulating cAMP signals during cardiac hypertrophy. The results of my investigations show that PDE2 activity is significantly increased in hypertrophic cardiac myocytes. In addition, I show that PDE2 activity is necessary to achieve full development of the catecholamine-induced hypertrophic response. In fact, pharmacological inhibition of PDE2 with Bay 60-7550 or genetic knock-down of PDE2 counteracts NE-induced cardiomyocytes hypertrophy. Remarkably, I found that increasing PDE2 activity by direct overexpression of the enzyme is sufficient to induce hypertrophic growth both in vitro and in vivo systems, even in the absence of increased adrenergic drive, thus indicating that PDE2 activity promotes development of cardiomyocytes hypertrophy. Given that PDE2 can degrade both cAMP and cGMP, I investigated whether the anti-hypertrophic effects of PDE2 inhibition are mediated by activation of the cGMP/PKG or the cAMP/PKA signalling pathways. The data presented here, show that the effects of pharmacological inhibition of PDE2 require PKA activity and suggest that NFAT may be the PKA target that mediates the anti-hypertrophic effects of Bay 60-7550. Data presented here also show that the specific subcellular localisation of PDE2 is critical for its control on hypertrophic growth. As demonstrated by the fact that displacement of PDE2 from its specific intracellular localisation is sufficient to counteract catecholamine-induced cardiac hypertrophy. All together, these findings demonstrate, for the first time, the involvement of PDE2 in the development of cardiac hypertrophy and indentify PDE2 as a possible novel therapeutic target to treat this condition.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: cAMP, PDE2, compartmentalisation, cardiac hypertrophy, FRET
• Subjects: R Medicine > RM Therapeutics. Pharmacology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Supervisor's Name: Zaccolo, Prof. Manuela
• Date of Award: 2012
• Embargo Date: 6 June 2015
• Depositing User: Anna Zoccarato
• Unique ID: glathesis:2012-3424
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 13 Jun 2012
• Last Modified: 10 Dec 2012 14:06
• URI: https://theses.gla.ac.uk/id/eprint/3424