ABSTRACT
BACKGROUND: Right ventricular (RV) failure is a major cause of mortality worldwide and is often a consequence of RV pressure overload (RVPO). Endoglin is a coreceptor for the profibrogenic cytokine, transforming growth factor beta 1 (TGF-ß1). TGF-ß1 signaling by the canonical transient receptor protein channel 6 (TRPC-6) was recently reported to stimulate calcineurin-mediated myofibroblast transformation, a critical component of cardiac fibrosis. We hypothesized that reduced activity of the TGF-ß1 coreceptor, endoglin, limits RV calcineurin expression and improves survival in RVPO. METHODS AND RESULTS: We first demonstrate that endoglin is required for TGF-ß1-mediated calcineurin/TRPC-6 expression and up-regulation of alpha-smooth muscle antigen (α-SMA), a marker of myofibroblast transformation, in human RV fibroblasts. Using endoglin haploinsufficient mice (Eng(+/-)) we show that reduced endoglin activity preserves RV function, limits RV fibrosis, and attenuates activation of the calcineurin/TRPC-6/α-SMA pathway in a model of angio-obliterative pulmonary hypertension. Next, using Eng(+/-) mice or a neutralizing antibody (Ab) against endoglin (N-Eng) in wild-type mice, we show that reduced endoglin activity improves survival and attenuates RV fibrosis in models of RVPO induced by pulmonary artery constriction. To explore the utility of targeting endoglin, we observed a reversal of RV fibrosis and calcineurin levels in wild-type mice treated with a N-Eng Ab, compared to an immunoglobulin G control. CONCLUSION: These data establish endoglin as a regulator of TGF-ß1 signaling by calcineurin and TRPC-6 in the RV and identify it as a potential therapeutic target to limit RV fibrosis and improve survival in RVPO, a common cause of death in cardiac and pulmonary disease.
Subject(s)
Calcineurin/genetics , Hypertension, Pulmonary/genetics , Intracellular Signaling Peptides and Proteins/genetics , RNA, Messenger/metabolism , TRPC Cation Channels/genetics , Ventricular Dysfunction, Right/genetics , Actins/genetics , Actins/metabolism , Animals , Antigens, CD/genetics , Antigens, CD/metabolism , Calcineurin/metabolism , Disease Models, Animal , Endoglin , Fibroblasts/metabolism , Heart Ventricles/cytology , Heart Ventricles/metabolism , Humans , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/physiopathology , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Mice, Knockout , Myofibroblasts/metabolism , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Signal Transduction , Survival Rate , TRPC Cation Channels/metabolism , TRPC6 Cation Channel , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolism , Ventricular Dysfunction, Right/metabolism , Ventricular Dysfunction, Right/physiopathologyABSTRACT
UNLABELLED: Right ventricular (RV) failure is a major cause of mortality in acute or chronic lung disease and left heart failure. The objective of this study was to demonstrate a percutaneous approach to study biventricular hemodynamics in murine models of primary and secondary RV pressure overload (RVPO) and further explore biventricular expression of two key proteins that regulate cardiac remodeling: calcineurin and transforming growth factor beta 1 (TGFß1). METHODS: Adult, male mice underwent constriction of the pulmonary artery or thoracic aorta as models of primary and secondary RVPO, respectively. Conductance catheterization was performed followed by tissue analysis for changes in myocyte hypertrophy and fibrosis. RESULTS: Both primary and secondary RVPO decreased biventricular stroke work however RV instantaneous peak pressure (dP/dtmax) and end-systolic elastance (Ees) were preserved in both groups compared to controls. In contrast, left ventricular (LV) dP/dtmax and LV-Ees were unchanged by primary, but reduced in the secondary RVPO group. The ratio of RV:LV ventriculo-arterial coupling was increased in primary and reduced in secondary RVPO. Primary and secondary RVPO increased RV mass, while LV mass decreased in primary and increased in the secondary RVPO groups. RV fibrosis and hypertrophy were increased in both groups, while LV fibrosis and hypertrophy were increased in secondary RVPO only. RV calcineurin expression was increased in both groups, while LV expression increased in secondary RVPO only. Biventricular TGFß1 expression was increased in both groups. CONCLUSION: These data identify distinct effects of primary and secondary RVPO on biventricular structure, function, and expression of key remodeling pathways.
