Abstract 10886: Targeting Endoglin Activity Improves Survival and Reduces Right Ventricular Fibrosis in a Murine Model of Pulmonary Arterial Hypertension
Right ventricular (RV) function is a major determinant of clinical outcomes in pulmonary hypertension (PH). Transforming growth factor beta1 (TGFb1) is a profibrogenic cytokine that signals via effector proteins known as Smads (canonical) and extracellular regulated kinases (ERK; non-canonical). We recently reported that reduced activity of the TGFb1 auxiliary receptor, endoglin (Eng), improves survival in a mouse model of left heart failure. The role of TGFb1/Eng signaling in RV remodeling remains unknown. We tested the hypothesis that PH-induced Eng expression augments TGFb1-activity and fibrosis in the RV, and that blocking endoglin activity limits RV fibrosis in PH.
Methods and Results: To explore the functional role of Eng in RV remodeling, pulmonary artery constriction (PAC) was performed in male,wild-type (WT) and Eng heterozygous (Eng+/-) mice. Compared to sham controls, PAC increased RV systolic pressure equally in both WT (21+6 vs 50+4, p<0.01) and Eng+/-(24+3 vs 46+9, p<0.01) mice. In WT mice, Eng mRNA and protein expression increased in the RV after 7 days of PAC accompanied by RV fibrosis and hypertrophy. In contrast to WT, Eng+/- mice had preserved RV stroke volume (4+1 vs 7+1, p<0.01) and cardiac output (1.9+0.7 vs 3.6+0.8 mL/min, p<0.01). Less RV fibrosis was observed in Eng+/- mice, while RV mass was comparable to WT after PAC. Despite similarly increased levels of active TGFb1 in the RV of WT and Eng+/- mice, levels of phosphorylated Smad-2/3 (pSmad-2/3) and pERK-1/2 were increased in the RV of WT mice, but unchanged in Eng+/- mice after PAC. The dependence of TGFb1 signaling on Eng expression was further tested using a neutralizing anti-endoglin antibody (TRC105; Tracon Pharma). Compared to IgG-treated controls, TRC105 limited RV fibrosis, pSmad-2/3 expression, and Type 1 Collagen expression in WT mice after PAC. Compared to WT, both Eng+/- and TRC105 treated mice had improved survival after PAC (60%; n=7/12 vs 100%; n=8/8 vs 88%; n=7/8, respectively, p<0.01 for Eng+/- or TRC105 mice vs WT).
Conclusion: These data identify endoglin as a critical component of TGFb1 signaling in RV responses to pressure overload and further identify endoglin as a potentially novel therapeutic target to limit TGFb1 activity, RV fibrosis, and improve survival in PH.
- © 2012 by American Heart Association, Inc.