PDE2-mediated cAMP hydrolysis accelerates cardiac fibroblast to myofibroblast conversion and is antagonized by exogenous activation of cGMP signaling pathways

Recent studies suggest that the signal molecules cAMP and cGMP have antifibrotic effects by negatively regulating pathways associated with fibroblast to myofibroblast (MyoCF) conversion. The phosphodiesterase 2 (PDE2) has the unique property to be stimulated by cGMP, which leads to a remarkable incr...

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Published in:	American journal of physiology. Heart and circulatory physiology Vol. 306; no. 8; p. H1246
Main Authors:	Vettel, C, Lämmle, S, Ewens, S, Cervirgen, C, Emons, J, Ongherth, A, Dewenter, M, Lindner, D, Westermann, D, Nikolaev, V O, Lutz, S, Zimmermann, W H, El-Armouche, A
Format:	Journal Article
Language:	English
Published:	United States 15-04-2014
Subjects:	Animals Animals, Newborn Atrial Natriuretic Factor - pharmacology Cells, Cultured Cyclic AMP - metabolism Cyclic GMP - physiology Cyclic Nucleotide Phosphodiesterases, Type 2 - genetics Cyclic Nucleotide Phosphodiesterases, Type 2 - physiology Fibroblasts - drug effects Fibroblasts - enzymology Fibroblasts - physiology Gene Expression Hydrolysis Myocardium - cytology Myocytes, Cardiac - enzymology Myofibroblasts - physiology Nitric Oxide Donors - pharmacology Nitroprusside - pharmacology Rats Receptors, Adrenergic, beta - physiology Signal Transduction - physiology cGMP phosphodiesterase 2 cAMP cardiac fibroblasts engineered connective tissue myofibroblast
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Summary:	Recent studies suggest that the signal molecules cAMP and cGMP have antifibrotic effects by negatively regulating pathways associated with fibroblast to myofibroblast (MyoCF) conversion. The phosphodiesterase 2 (PDE2) has the unique property to be stimulated by cGMP, which leads to a remarkable increase in cAMP hydrolysis and thus mediates a negative cross-talk between both pathways. PDE2 has been recently investigated in cardiomyocytes; here we specifically addressed its role in fibroblast conversion and cardiac fibrosis. PDE2 is abundantly expressed in both neonatal rat cardiac fibroblasts (CFs) and cardiomyocytes. The overexpression of PDE2 in CFs strongly reduced basal and isoprenaline-induced cAMP synthesis, and this decrease was sufficient to induce MyoCF conversion even in the absence of exogenous profibrotic stimuli. Functional stress-strain experiments with fibroblast-derived engineered connective tissue (ECT) demonstrated higher stiffness in ECTs overexpressing PDE2. In regard to cGMP, neither basal nor atrial natriuretic peptide-induced cGMP levels were affected by PDE2, whereas the response to nitric oxide donor sodium nitroprusside was slightly but significantly reduced. Interestingly, despite persistently depressed cAMP levels, both cGMP-elevating stimuli were able to completely prevent the PDE2-induced MyoCF phenotype, arguing for a double-tracked mechanism. In conclusion, PDE2 accelerates CF to MyoCF conversion, which leads to greater stiffness in ECTs. Atrial natriuretic peptide- and sodium nitroprusside-mediated cGMP synthesis completely reverses PDE2-induced fibroblast conversion. Thus PDE2 may augment cardiac remodeling, but this effect can also be overcome by enhanced cGMP. The redundant role of cAMP and cGMP as antifibrotic meditators may be viewed as a protective mechanism in heart failure.
ISSN:	1522-1539
DOI:	10.1152/ajpheart.00852.2013