Document Detail

Reduced endoglin activity limits cardiac fibrosis and improves survival in heart failure.
MedLine Citation:
PMID:  22592898     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Heart failure is a major cause of morbidity and mortality worldwide. The ubiquitously expressed cytokine transforming growth factor-β1 (TGFβ1) promotes cardiac fibrosis, an important component of progressive heart failure. Membrane-associated endoglin is a coreceptor for TGFβ1 signaling and has been studied in vascular remodeling and preeclampsia. We hypothesized that reduced endoglin expression may limit cardiac fibrosis in heart failure.
METHODS AND RESULTS: We first report that endoglin expression is increased in the left ventricle of human subjects with heart failure and determined that endoglin is required for TGFβ1 signaling in human cardiac fibroblasts using neutralizing antibodies and an siRNA approach. We further identified that reduced endoglin expression attenuates cardiac fibrosis, preserves left ventricular function, and improves survival in a mouse model of pressure-overload-induced heart failure. Prior studies have shown that the extracellular domain of endoglin can be cleaved and released into the circulation as soluble endoglin, which disrupts TGFβ1 signaling in endothelium. We now demonstrate that soluble endoglin limits TGFβ1 signaling and type I collagen synthesis in cardiac fibroblasts and further show that soluble endoglin treatment attenuates cardiac fibrosis in an in vivo model of heart failure.
CONCLUSION: Our results identify endoglin as a critical component of TGFβ1 signaling in the cardiac fibroblast and show that targeting endoglin attenuates cardiac fibrosis, thereby providing a potentially novel therapeutic approach for individuals with heart failure.
Navin K Kapur; Szuhuei Wilson; Adil A Yunis; Xiaoying Qiao; Emily Mackey; Vikram Paruchuri; Corey Baker; Mark J Aronovitz; S Ananth Karumanchi; Michelle Letarte; David A Kass; Michael E Mendelsohn; Richard H Karas
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-05-16
Journal Detail:
Title:  Circulation     Volume:  125     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-06-05     Completed Date:  2012-09-13     Revised Date:  2014-11-16    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2728-38     Citation Subset:  AIM; IM    
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MeSH Terms
Antibodies / pharmacology
Antigens, CD / metabolism*
Collagen Type I / metabolism
Disease Models, Animal
Fibroblasts / drug effects,  metabolism,  pathology
Heart Failure / metabolism*,  mortality*,  physiopathology
Heart Ventricles / metabolism,  pathology,  physiopathology
Intracellular Signaling Peptides and Proteins / metabolism*
Mice, Inbred C57BL
Myocardium / metabolism*,  pathology*
RNA, Small Interfering / pharmacology
Receptors, Cell Surface / metabolism*
Signal Transduction / physiology
Survival Rate
Transforming Growth Factor beta1 / metabolism
Grant Support
Reg. No./Substance:
0/Antibodies; 0/Antigens, CD; 0/Collagen Type I; 0/ENG protein, human; 0/Intracellular Signaling Peptides and Proteins; 0/RNA, Small Interfering; 0/Receptors, Cell Surface; 0/Transforming Growth Factor beta1; 0/endoglin protein, mouse
Comment In:
Circulation. 2012 Jun 5;125(22):2689-91   [PMID:  22592899 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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