title: Reduced endoglin activity limits cardiac fibrosis and improves survival in heart failure.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, 800 Washington St, Box 80, Boston, MA 02111, USA. Nkapur@tuftsmedicalcenter.org
authors.forename: Navin K
authors.initials: NK
authors.lastname: Kapur
authors.forename: Szuhuei
authors.initials: S
authors.lastname: Wilson
authors.forename: Adil A
authors.initials: AA
authors.lastname: Yunis
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Qiao
authors.forename: Emily
authors.initials: E
authors.lastname: Mackey
authors.forename: Vikram
authors.initials: V
authors.lastname: Paruchuri
authors.forename: Corey
authors.initials: C
authors.lastname: Baker
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Aronovitz
authors.forename: S Ananth
authors.initials: SA
authors.lastname: Karumanchi
authors.forename: Michelle
authors.initials: M
authors.lastname: Letarte
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.forename: Michael E
authors.initials: ME
authors.lastname: Mendelsohn
authors.forename: Richard H
authors.initials: RH
authors.lastname: Karas
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D000071063:Endoglin; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D006333:Heart Failure / Q000378:metabolism* / Q000401:mortality* / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D015996:Survival Rate; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D024042:Collagen Type I; C064206:ENG protein, human; D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D053773:Transforming Growth Factor beta1