| Property | Value |
|---|
| Working Groups |  AG El-Armouche,  AG Lutz,  AG Nikolaev,  AG Zimmermann |
| Subproject | A02, C04 |
| Open Access | No |
| Publication Type | Journal Article |
| Peer Reviewed | Unknown |
| PMID |  24531807 |
| DOI |  10.1152/ajpheart.00852.2013 |
| Publication Year | 2014 |
| Title | PDE2-mediated cAMP hydrolysis accelerates cardiac fibroblast to myofibroblast conversion and is antagonized by exogenous activation of cGMP signaling pathways  |
| Journal | American Journal of Physiology-Heart and Circulatory Physiology |
| ISSN | 0363-6135 |
| eISSN | 1522-1539 |
| URL | http://ajpheart.physiology.org/content/306/8/H1246 |
| Pages | H1246-H1252 |
| Issue | 8 |
| Volume | 306 |
| Journal Abbreviation | Am J Physiol-Heart Circul Physiol |
| Extra | 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. PMID: 24531807 |
| Authors | Vettel C, Lämmle S, Ewens S, Cervirgen C, Emons J, Ongherth A, Dewenter M, Lindner D, Westermann D, Nikolaev VO, Lutz S, Zimmermann WH, El-Armouche A |
| First Author | Vettel C |
| Last Author | El-Armouche A |
| Scholia |  Wikidata-based representation at Scholia |
External Resources
journals...2.2013https://journals.physiology.org/doi/pdf/10.1152/ajpheart.00852.2013
Article fulltext
gro-2/5133http://resolver.sub.uni-goettingen.de/purl?gro-2/5133
GRO.publications identifier
10114https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?id=10114
NCBI Taxonomy (Rattus)
NM_001008548.3https://www.ncbi.nlm.nih.gov/nuccore/NM_001008548.3
NCBI nucleotide (NM_001008548.3)
0000-0002-7529-5179https://orcid.org/0000-0002-7529-5179
ORCID identifier (Viacheslav O. Nikolaev)
0000-0002-0554-8070https://orcid.org/0000-0002-0554-8070
ORCID identifier (Susanne Lutz)
0000-0003-1190-4040https://orcid.org/0000-0003-1190-4040
ORCID identifier (Wolfram-Hubertus Zimmermann)
021ft0n22https://ror.org/021ft0n22
ROR identifier (021ft0n22, University Medical Center Göttingen)
031t5w623https://ror.org/031t5w623
ROR identifier (031t5w623, German Centre for Cardiovascular Research)
Q42454314https://www.wikidata.org/wiki/Q42454314
Wikidata ID
