title: Histone deacetylase inhibition with trichostatin A does not reverse severe angioproliferative pulmonary hypertension in rats (2013 Grover Conference series).
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.
authors.affiliation: Department of Pulmonology, Pulmonary Arterial Hypertension Knowledge Centre, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Michiel Alexander
authors.initials: MA
authors.lastname: De Raaf
authors.affiliation: Pulmonary and Critical Care Medicine Division, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Aysar Al
authors.initials: AA
authors.lastname: Hussaini
authors.affiliation: Pulmonary and Critical Care Medicine Division, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Gomez-Arroyo
authors.affiliation: Pulmonary and Critical Care Medicine Division, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Donatas
authors.initials: D
authors.lastname: Kraskaukas
authors.affiliation: Pulmonary and Critical Care Medicine Division, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Farkas
authors.affiliation: Department of Pulmonology, Pulmonary Arterial Hypertension Knowledge Centre, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Chris
authors.initials: C
authors.lastname: Happé
authors.affiliation: Pulmonary and Critical Care Medicine Division, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Voelkel
authors.affiliation: Department of Pulmonology, Pulmonary Arterial Hypertension Knowledge Centre, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Harm Jan
authors.initials: HJ
authors.lastname: Bogaard
keywords: HDAC activity; HDAC inhibitors; experimental pulmonary hypertension