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Chronic inhibition of cyclic guanosine monophosphate-specific phosphodiesterase 5 prevented cardiac fibrosis through inhibition of transforming growth factor β-induced Smad signaling.
MedLine Citation:
PMID:  25416030     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Recent evidences suggested that cyclic guanosine monophosphate-specific phosphodiesterase 5 (PDE5) inhibitor represents an important therapeutic target for cardiovascular diseases. Whether and how it ameliorates cardiac fibrosis, a major cause of diastolic dysfunction and heart failure, is unknown. The purpose of this study was to investigate the effects of PDE5 inhibitor on cardiac fibrosis. We assessed cardiac fibrosis and pathology in mice subjected to transverse aortic constriction (TAC). Oral sildenafil, a PDE5 inhibitor, was administered in the therapy group. In control mice, 4 weeks of TAC induced significant cardiac dysfunction, cardiac fibrosis, and cardiac fibroblast activation (proliferation and transformation to myofibroblasts). Sildenafil treatment markedly prevented TAC-induced cardiac dysfunction, cardiac fibrosis and cardiac fibroblast activation but did not block TAC-induced transforming growth factor-β1 (TGF-β1) production and phosphorylation of Smad2/3. In isolated cardiac fibroblasts, sildenafil blocked TGF-β1-induced cardiac fibroblast transformation, proliferation and collagen synthesis. Furthermore, we found that sildenafil induced phosphorylated cAMP response element binding protein (CREB) and reduced CREB-binding protein 1 (CBP1) recruitment to Smad transcriptional complexes. PDE5 inhibition prevents cardiac fibrosis by reducing CBP1 recruitment to Smad transcriptional complexes through CREB activation in cardiac fibroblasts.
Authors:
Wei Gong; Mengwen Yan; Junxiong Chen; Sandip Chaugai; Chen Chen; Daowen Wang
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-11-22
Journal Detail:
Title:  Frontiers of medicine     Volume:  -     ISSN:  2095-0225     ISO Abbreviation:  Front Med     Publication Date:  2014 Nov 
Date Detail:
Created Date:  2014-11-22     Completed Date:  -     Revised Date:  2014-11-25    
Medline Journal Info:
Nlm Unique ID:  101549428     Medline TA:  Front Med     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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