Reduced endoglin activity limits cardiac fibrosis and improves survival in 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

Research output: Contribution to journalArticle

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. 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.

Original languageEnglish (US)
Pages (from-to)2728-2738
Number of pages11
JournalCirculation
Volume125
Issue number22
DOIs
StatePublished - Jun 5 2012

Keywords

  • Fibrosis
  • Heart failure
  • Ventricular remodeling

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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  • Cite this

    Kapur, N. K., Wilson, S., Yunis, A. A., Qiao, X., MacKey, E., Paruchuri, V., Baker, C., Aronovitz, M. J., Karumanchi, S. A., Letarte, M., Kass, D. A., Mendelsohn, M. E., & Karas, R. H. (2012). Reduced endoglin activity limits cardiac fibrosis and improves survival in heart failure. Circulation, 125(22), 2728-2738. https://doi.org/10.1161/CIRCULATIONAHA.111.080002