Document Detail


Reduced Endoglin Activity Limits Cardiac Fibrosis and Improves Survival in Heart Failure.
MedLine Citation:
PMID:  22592898     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
BACKGROUND: Heart failure is a major cause of morbidity and mortality worldwide. The ubiquitously expressed cytokine, transforming growth factor beta-1 (TGFβ1), promotes cardiac fibrosis, an important component of progressive heart failure. Membrane-associated endoglin is a co-receptor 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 (LV) of human subjects with heart failure and determined that endoglin is required for TGFβ1 signaling in human cardiac fibroblasts using neutralizing antibodies and a siRNA approach. We further identified that reduced endoglin expression attenuates cardiac fibrosis, preserves LV 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 (sEng), which disrupts TGFβ1 signaling in endothelium. We now demonstrate that sEng limits TGFβ1 signaling and Type I collagen synthesis in cardiac fibroblasts and further show that sEng treatment attenuates cardiac fibrosis in an in vivo model of heart failure. CONCLUSIONS: Our results identify endoglin as a critical component of TGFβ1 signaling in the cardiac fibroblast and that targeting endoglin attenuates cardiac fibrosis, thereby providing a potentially novel therapeutic approach for individuals with heart failure.
Authors:
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     Date:  2012-5-16
Journal Detail:
Title:  Circulation     Volume:  -     ISSN:  1524-4539     ISO Abbreviation:  -     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-5-17     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
1 Tufts Medical Center & Tufts University School of Medicine, Boston, MA;
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