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.

Rationale: Intermittent hypoxia (IH) is one of the main features of sleep-disordered breathing (SDB). Recent findings indicate that hypoxia inducible factor-1 (HIF-1) promotes cardiomyocytes apoptosis during chronic IH, but the mechanisms involved remain to be elucidated. Here, we hypothesize that IH-induced ER stress is associated with mitochondria-associated ER membrane (MAM) alteration and mitochondrial dysfunction, through HIF-1 activation. Methods: Right atrial appendage biopsies from patients with and without SDB were used to determine HIF-1α, Grp78 and CHOP expressions. Wild-type and HIF-1α^+/− mice were exposed to normoxia (N) or IH (21–5% O₂, 60 cycles/h, 8 h/day) for 21 days. Expressions of HIF-1α, Grp78 and CHOP, and apoptosis, were measured by Western blot and immunochemistry. In isolated cardiomyocytes, we examined structural integrity of MAM by proximity ligation assay and their function by measuring ER-to-mitochondria Ca²⁺ transfer by confocal microscopy. Finally, we measured mitochondrial respiration using oxygraphy and calcium retention capacity (CRC) by spectrofluorometry. MAM structure was also investigated in H9C2 cells incubated with 1 mM CoCl₂, a potent HIF-1α inducer. Results: In human atrial biopsies and mice, IH induced HIF-1 activation, ER stress and apoptosis. IH disrupted MAM, altered Ca²⁺ homeostasis, mitochondrial respiration and CRC. Importantly, IH had no effect in HIF-1α^+/− mice. Similar to what observed under IH, HIF-1α overexpression was associated with MAM alteration in H9C2. Conclusion: IH-induced ER stress, MAM alterations and mitochondrial dysfunction were mediated by HIF-1; all these intermediate mechanisms ultimately inducing cardiomyocyte apoptosis. This suggests that HIF-1 modulation might limit the deleterious cardiac effects of SDB.

The Spontaneous Physical Activity (SPA) can be responsible for variations of a lot of physiological parameters at the molecular, cellular, tissue, and systemic levels. It is increasingly recognized that the good understanding of a large part of laboratory experimentations, implies to weight results by this SPA in order to reduce the variability, and so to decrease the number of animals necessary to conduct a study. However, because of the high cost of these equipment, only few laboratories are equipped with such a device to measure the SPA of their animals. Here, we present an effective, adaptable and low-cost system to measure SPA in rodents, based on a video acquisition of the animal in his own environment.

It is now well established that the intrauterine life environment is of major importance for health during later life. Endurance training during pregnancy is associated with positive metabolic adjustments and beneficial effects on the balance between pro and antioxidant (redox state) in the offspring. Our hypothesis is that these changes could rely on mitochondrial adaptations in the offspring due to modifications of the fetal environment induced by maternal endurance training. Therefore, we compared the liver and skeletal muscle mitochondrial function and the redox status of young rats whose mothers underwent moderate endurance training (treadmill running) before and during gestation (T) to those of young rats from untrained mothers (C). Our results show a significant reduction in the spontaneous H₂O₂ release by liver and muscle mitochondria in the T vs. C rats (p<0.05). These changes are accompanied by alterations in oxygen consumption. Moreover, the percentage of short chain fatty acids increased significantly, in liver mitochondria from T rats. This may lead to improve the fluidity and the flexibility of the membrane. In plasma, GPX activity and protein oxidation are significantly higher in T rats compared to C rats (p<0.05). Such changes in plasma could represent an adaptive signal transmitted from mothers to their offspring. We demonstrated for the first time, to our knowledge, that it is possible to act on the bioenergetic functionning including alterations of the mitochondrial function in the offspring by modifying maternal physical activity before and during pregnancy. These changes could be crucial for the future health of the offspring.