Histone deacetylase inhibition with trichostatin A does not reverse severe angioproliferative pulmonary hypertension in rats (2013 Grover Conference series)

PVRI Member Authors: Michiel Alexander de Raaf, Norbert Voelkel, Harm-Jan Bogaard

Abstract

Pulmonary arterial hypertension (PAH) is a rapidly progressive and devastating disease characterized by remodeling of lung vessels, increased pulmonary vascular resistance, and eventually right ventricular hypertrophy and failure. Because histone deacetylase (HDAC) inhibitors are agents hampering tumor growth and cardiac hypertrophy, they have been attributed a therapeutic potential for patients with PAH. Outcomes of studies evaluating the use of HDAC inhibitors in models of PAH and right ventricular pressure overload have been equivocal, however. Here we describe the levels of HDAC activity in the lungs and hearts of rats with pulmonary hypertension and right heart hypertrophy or failure, experimentally induced by monocrotaline (MCT), the combined exposure to the VEGF-R inhibitor SU5416 and hypoxia (SuHx), and pulmonary artery banding (PAB). We show that HDAC activity levels are reduced in the lungs of rat with experimentally induced hypertension, whereas activity levels are increased in the hypertrophic hearts. In contrast to what was previously found in the MCT model, the HDAC inhibitor trichostatin A had no effect on pulmonary vascular remodeling in the SuHx model. When our results and those in the published literature are taken together, it is suggested that the effects of HDAC inhibitors in humans with PAH and associated RV failure are, at best, unpredictable. Significant progress can perhaps be made by using more specific HDAC inhibitors, but before clinical tests in human PAH can be undertaken, careful preclinical studies are required to determine potential cardiotoxicity.

Read the full article online

Topics

Animal Models
Apoptosis
Cell Biochemistry and Metabolism, Differentiation and Proliferation, Structure and Function, interactions
Endothelin and Endothelium & Epithelium and Epithelial Transport
Pulmonary Arterial Hypertension
Pulmonary Endothelium
Pulmonary Hypertension

Authors

Michiel Alexander De Raaf, Aysar Al Hussaini, Jose Gomez-Arroyo, Donatas Kraskaukas, Daniela Farkas, Chris Happé, Norbert F. Voelkel, Harm Jan Bogaard

Published in:

Pulmonary Circulation Vol 4: No 2 cover image

May 2014

Pulmonary Circulation Vol 4: 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