Endoglin: A Novel Target of Therapy for Right Heart Failure

Tufts Medical Center, Boston MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): This revised RO1 proposal explores the mechanisms regulating right ventricular (RV) failure, a major cause of morbidity and mortality for patients wih left heart failure and lung disease. Based on exciting new data generated with support from the NIH-KO8 program, we will explore the role of endoglin, an auxiliary receptor for the pro-fibrogenic cytokine transforming growth factor beta (TGFb1), as a regulator of maladaptive RV remodeling. The PI is an advanced heart failure and invasive hemodynamic specialist, whose laboratory studies molecular mechanisms regulating TGFb1 and endoglin activity using preclinical models of heart failure and human tissue samples. The Kapur laboratory recently published data showing that endoglin facilitates TGFb1-mediated left ventricular (LV) fibrosis, and further, that reduced endoglin expression improves survival in left heart failure. The current proposal applies this expertise in TGFb1/endoglin biology, hemodynamics, and heart failure to the field of RV failure, for which no specific therapy currently exists. This revised version of th proposal introduces a novel signaling pathway involving endoglin-dependent regulation of calcineurin-mediated myofibroblast transformation that selectively occurs in the RV, not LV. Preliminary data included in the proposal shows that reduced endoglin activity improves survival, attenuates RV fibrosis, and limits RV expression of calcineurin and the canonical transient receptor protein channel-6 (TRPC-6), key mediators of pathologic cardiac remodeling. The proposal is further strengthened by new data showing (a) endoglin- dependent effects on calcium handling in RV fibroblasts, (b) distinct RV and LV responses to chronic pressure overload, (c) increased RV endoglin levels in models of RV pressure overload and pharmacologically triggered pulmonary arterial hypertension (PAH), and (d) the use of a neutralizing endoglin antibody currently being tested in cancer therapeutics. These data and the development of transgenic models of targeted endoglin deletion and pioneering methods to analyze biventricular pressure-volume loops in mice provide exciting approaches to test the central hypothesis that heart failure and lung disease increase endoglin expression in the RV, which promotes maladaptive remodeling and further that reducing endoglin activity selectively limits calcineurin/TRPC-6 expression in the RV, not LV, thereby attenuating RV failure and improving survival in the setting of RV injury. To test this hypothesis three aims are proposed: (Aim 1) Determine the signaling mechanisms underlying endoglin-dependent regulation of calcineurin and TRPC-channel activity; (Aim 2) Determine the mechanisms underlying endoglin-dependent regulation of cardiac remodeling in models of RV pressure overload and PAH; (Aim 3) Determine the therapeutic utility of targeting endoglin activity in RV failure. The proposal opens an exciting new avenue for exploration that implicates endoglin as a master switch governing maladaptive signaling in the RV. This highly translational proposal will generate significant insight into RV failure and may lead to new approaches for this debilitating condition.