Reduced Endoglin Activity Limits Cardiac Fibrosis and Improves Survival in Heart Failure

Background-Heart failure is a major cause of morbidity and mortality worldwide. The ubiquitously expressed cytokine transforming growth factor-beta 1 (TGF beta 1) promotes cardiac fibrosis, an important component of progressive heart failure. Membrane-associated endoglin is a coreceptor for TGF beta 1 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 TGF beta 1 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 TGF beta 1 signaling in endothelium. We now demonstrate that soluble endoglin limits TGF beta 1 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 TGF beta 1 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. (Circulation. 2012; 125: 2728-2738.)