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.

Keywords: HDAC activity; HDAC inhibitors; experimental pulmonary hypertension.

Figure 1

Histone deacetylase (HDAC) activity was decreased in lung tissue (A) of monocrotaline (MCT)– and Sugen hypoxia (SuHx)–exposed rats. Lung tissue after pulmonary artery banding (PAB) was not affected. HDAC activity was increased in the pressure-overloaded right ventricle of all experimental models used (B). Comparisons with controls are denoted by *(P < .05), **(P < .01), and ***(P < .001).

Figure 2

Echocardiographic assessment and Fulton index of control rats and rats exposed to Sugen hypoxia (SuHx), with or without treatment with trichostatin A (TSA). Tricuspid annular plane systolic excursion (TAPSE), right ventricular inner diameter (RVID/d), and right ventricular systolic pressure (RVSP) were altered because of the induction of experimental pulmonary hypertension by SuHx, but no differences were seen between the SuHx group and SuHx group with TSA treatment. The Fulton index showed similar results. Comparisons with controls are denoted by *(P < .05) and **(P < .01).

Figure 3

Pulmonary vessel remodeling was seen in rats exposed to Sugen and hypoxia (SuHx) and consisted of medial hypertrophy and intima hyperproliferative lesions in small arteries (indicated by arrowheads and arrows). Trichostatin A (TSA) treatment in SuHx rats did not affect pulmonary vessel remodeling (as shown in the column labeled SuHx + TSA). Hematoxylin and eosin staining; top two rows = original magnification ×40; bottom row = original magnification ×200.

Figure 4

The physiological response on histone deacetylase (HDAC) activity (blue) decreases in the lung (left panel), whereas cardiac HDAC activity (right panel) increases (blue) upon different experimental PH exposures. Treatment of HDAC inhibitors (HDACi) was beneficial in hypoxia (and monocrotaline; green), was neither worsening nor beneficial in sugen hypoxia (orange), and was detrimental for pulmonary artery banding in the heart (red). Bogaard = Bogaard et al.; Cavasin = Cavasin et al.; PAB = pulmonary artery banding; SuHx = Sugen and hypoxia; Zhao = Zhao et al.