This new early stage investigator RO1 proposal explores new mechanisms regulating cardiac fibrosis, a major cause of morbidity and mortality for patients with heart failure (HF) Based on exciting new data generated with support from the NIH-KO8 program, we will explore a new mechanism for the role of endoglin, an auxiliary receptor for the pro-fibrogenic cytokine transforming growth factor beta (TGFb1), as a mediator of maladaptive cardiac remodeling. The PI is an advanced HF specialist, whose laboratory studies molecular mechanisms regulating TGFb1 and endoglin activity using preclinical models of HF and human tissue. The Kapur laboratory recently reported that endoglin facilitates TGFb1-mediated left and right ventricular (LV and RV) fibrosis, and further, that reduced endoglin expression improves survival in models of LV and RV failure. More recent data support that endoglin is required for signaling via bone morphogenetic protein 9 (BMP9) in endothelium, however a role for BMP9 in HF has not been explored. The current proposal applies expertise in endoglin biology, hemodynamics, and HF to the field of TGFb-mediated cardiac fibrosis, for which no specific therapy currently exists. This proposal tests the novel hypothesis that endoglin promotes cardiac fibrosis by negatively regulating BMP9, a new endogenous inhibitor of TGFb1-mediated collagen synthesis in cardiac fibroblasts, and further that reducing endoglin activity selectively increases BMP9 abundance, thereby limiting cardiac fibrosis and improving survival in HF. Preliminary data included in the proposal shows that 1) endoglin and BMP9 are highly expressed by non-myocyte cell populations in the heart, 2) endoglin negatively regulates BMP9 expression in human cardiac fibroblasts (hCF), 3) BMP9 inhibits TGFb1 mediated collagen synthesis in hCF, 4) loss of BMP9 promotes LV fibrosis after TAC, 5) reduced endoglin activity increases BMP9 abundance in the LV, and 6) neutralizing endoglin can reverse established cardiac fibrosis. Innovative aspects of the proposal include: (a) the use of hCF for in vitro studies, (b) transgenic mice developed specifically to study endoglin and BMP9 in HF, (c) pioneering techniques to study composition and mechanical properties of the extracellular matrix, and d) studies to test the translational potential of targeting endoglin and BMP9 activity in HF. To test this hypothesis three aims are proposed: (SA1) Determine the mechanisms underlying endoglin- dependent regulation of BMP9 signaling in hCF; (SA2) Determine the mechanisms underlying endoglin- dependent regulation of maladaptive remodeling in HF; (SA3) Test the utility of targeting endoglin/BMP9 activity to reverse established cardiac fibrosis in HF. This proposal explores a paradigm shifting hypothesis that has tremendous potential to impact our basic understanding of cardiac fibroblast physiology, TGFb superfamily signaling, and cardiac remodeling with important implications for the growing population of patients with HF.
Cardiac fibrosis is a major component of adverse cardiac remodeling that occurs in millions of individuals suffering from heart failure. Transforming growth factor beta 1 (TGFb1) is one of the most potent pro- fibrogenic cytokines in heart failure. At present, no therapies to specifically block TGFb1 activity in heart failure exist due in part to the ubiquitous nature of this important cytokine. This project explores a new signaling pathway regulating cardiac fibrosis that is governed by a protein known as endoglin. Based on extensive new data, we have identified that endoglin negatively regulates a protein known as bone morphogenetic protein 9 (BMP9), a cytokine that inhibits TGFb1 mediated collagen synthesis in cardiac fibroblasts. The project holds great promise for the design of new therapies that reduce morbidity and improve survival in patients with heart failure.
|Morine, Kevin J; Qiao, Xiaoying; York, Sam et al. (2018) Bone Morphogenetic Protein 9 Reduces Cardiac Fibrosis and Improves Cardiac Function in Heart Failure. Circulation 138:513-526|
|Morine, Kevin J; Qiao, Xiaoying; Paruchuri, Vikram et al. (2017) Reduced activin receptor-like kinase 1 activity promotes cardiac fibrosis in heart failure. Cardiovasc Pathol 31:26-33|
|Kapur, Navin K; Davila, Carlos D; Jumean, Marwan F (2017) Integrating Interventional Cardiology and Heart Failure Management for Cardiogenic Shock. Interv Cardiol Clin 6:481-485|
|Morine, Kevin J; Qiao, Xiaoying; Paruchuri, Vikram et al. (2017) Conditional knockout of activin like kinase-1 (ALK-1) leads to heart failure without maladaptive remodeling. Heart Vessels 32:628-636|