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Int J Mol Sci. 2018 Jul 30;19(8). pii: E2224. doi: 10.3390/ijms19082224.

Inhibition of BET Proteins Reduces Right Ventricle Hypertrophy and Pulmonary Hypertension Resulting from Combined Hypoxia and Pulmonary Inflammation.

Author information

1
Université Grenoble Alpes, Inserm U1055, Laboratoire de Bioénergétique Fondamentale et Appliquée, 38058 Grenoble, France. clovis.chabert@gmail.com.
2
CNRS UMR 5309, Inserm U1209, Université Grenoble Alpes, Institute for Advanced Biosciences, 38700 Grenoble, France. saadi.khochbin@univ-grenoble-alpes.fr.
3
CNRS UMR 5309, Inserm U1209, Université Grenoble Alpes, Institute for Advanced Biosciences, 38700 Grenoble, France. sophie.rousseaux@univ-grenoble-alpes.fr.
4
Université Grenoble Alpes, CNRS UMR 5553, Laboratoire d'Ecologie Alpine, 38058 Grenoble, France. sylvie.veyrenc@univ-grenoble-alpes.fr.
5
Epigenetics DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline R&D, Medicines Research Centre, Stevenage SG1 2NY, UK. rebecca.c.furze@gsk.com.
6
Epigenetics DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline R&D, Medicines Research Centre, Stevenage SG1 2NY, UK. nick.n.smithers@gsk.com.
7
Epigenetics DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline R&D, Medicines Research Centre, Stevenage SG1 2NY, UK. Rabinder.Prinjha@gsk.com.
8
Université Grenoble Alpes, Inserm U1055, Laboratoire de Bioénergétique Fondamentale et Appliquée, 38058 Grenoble, France. uwe.schlattner@univ-grenoble-alpes.fr.
9
Université Grenoble Alpes, Inserm U1055, Laboratoire de Bioénergétique Fondamentale et Appliquée, 38058 Grenoble, France. CPison@chu-grenoble.fr.
10
Centre Hospitalier Universitaire Grenoble Alpes, Université Grenoble Alpes, 38700 Grenoble, France. CPison@chu-grenoble.fr.
11
Université Grenoble Alpes, Inserm U1055, Laboratoire de Bioénergétique Fondamentale et Appliquée, 38058 Grenoble, France. herve.dubouchaud@univ-grenoble-alpes.fr.

Abstract

Pulmonary hypertension is a co-morbidity, which strongly participates in morbi-mortality in patients with chronic obstructive pulmonary disease (COPD). Recent findings showed that bromodomain-containing proteins, in charge of reading histone acetylation, could be involved in pulmonary arterial hypertension. Our aim was to study the effect of I-BET151, an inhibitor of bromodomain and extra-terminal domain (BET), on the right ventricle hypertrophy and pulmonary hypertension, induced by a combination of chronic hypoxia and pulmonary inflammation, as the two main stimuli encountered in COPD. Adult Wistar male rats, exposed to chronic hypoxia plus pulmonary inflammation (CHPI), showed a significant right ventricle hypertrophy (+57%, p < 0.001), an increase in systolic pressure (+46%, p < 0.001) and in contraction speed (+36%, p < 0.001), when compared to control animals. I-BET151 treated animals (CHPI-iB) showed restored hemodynamic parameters to levels similar to control animals, despite chronic hypoxia plus exposure to pulmonary inflammation. They displayed lower right ventricle hypertrophy and hematocrit compared to the CHPI group (respectively -16%, p < 0.001; and -9%, p < 0.05). Our descriptive study shows a valuable effect of the inhibition of bromodomain and extra-terminal domain proteins on hemodynamic parameters, despite the presence of chronic hypoxia and pulmonary inflammation. This suggests that such inhibition could be of potential interest for COPD patients with pulmonary hypertension. Further studies are needed to unravel the underlying mechanisms involved and the net benefits of inhibiting adaptations to chronic hypoxia.

KEYWORDS:

COPD; Epigenetic; hypoxia; pulmonary hypertension; pulmonary inflammation

PMID:
30061518
PMCID:
PMC6121304
DOI:
10.3390/ijms19082224
[Indexed for MEDLINE]
Free PMC Article

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