Antagonism of the thromboxane-prostanoid receptor is cardioprotective against right ventricular pressure overload

PVRI Member Authors: James West, Anna Hemnes

Abstract

Right ventricular (RV) failure is the primary cause of death in pulmonary arterial hypertension (PAH) and is a significant cause of morbidity and mortality in other forms of pulmonary hypertension. There are no approved therapies directed at preserving RV function. F-series and E-series isoprostanes are increased in heart failure and PAH, correlate to the severity of disease, and can signal through the thromboxane-prostanoid (TP) receptor, with effects from vasoconstriction to fibrosis. The goal of these studies was to determine whether blockade of the TP receptor with the antagonist CPI211 was beneficial therapeutically in PAH-induced RV dysfunction. Mice with RV dysfunction due to pressure overload by pulmonary artery banding (PAB) were given vehicle or CPI211. Two weeks after PAB, CPI211-treated mice were protected from fibrosis with pressure overload. Gene expression arrays and immunoblotting, quantitative histology and morphometry, and flow cytometric analysis were used to determine the mechanism of CPI211 protection. TP receptor inhibition caused a near normalization of fibrotic area, prevented cellular hypertrophy while allowing increased RV mass, increased expression of antifibrotic thrombospondin-4, and blocked induction of the profibrotic transforming growth factor β (TGF-β) pathway. A thromboxane synthase inhibitor or low-dose aspirin failed to replicate these results, which suggests that a ligand other than thromboxane mediates fibrosis through the TP receptor after pressure overload. This study suggests that TP receptor antagonism may improve RV adaptation in situations of pressure overload by decreasing fibrosis and TGF-β signaling.

Read the full article online

Topics

Pulmonary Arterial Hypertension
Right Ventricle: Structure, Function and Dysfunction

Authors

James D. West, Bryan M. Voss, Leo Pavliv, Mark de Caestecker, Anna R. Hemnes, Erica J. Carrier

Published in:

Pulmonary Circulation Vol 6: No 2 cover image

June 2016

Pulmonary Circulation Vol 6: No 2

View this journal

Our research platform is the world.

Through worldwide collaboration, we can begin to answer the question of a global disease.

Join the PVRI
standard-example-image.jpg