Proteomic remodeling of proteasome in right heart failure.

The development of right heart failure (RHF) is characterized by alterations of right ventricle (RV) structure and function, but the mechanisms of RHF remain still unknown. Thus, understanding the RHF is essential for improved therapies. Therefore, identification by quantitative proteomics of targets specific to RHF may have therapeutic benefits to identify novel potential therapeutic targets. The objective of this study was to analyze the molecular mechanisms changing RV function in the diseased RHF and thus, to identify novel potential therapeutic targets. For this, we have performed differential proteomic analysis of whole RV proteins using two experimental rat models of RHF. Differential protein expression was observed for hundred twenty six RV proteins including proteins involved in structural constituent of cytoskeleton, motor activity, structural molecule activity, cytoskeleton protein binding and microtubule binding. Interestingly, further analysis of down-regulated proteins, reveals that both protein and gene expressions of proteasome subunits were drastically decreased in RHF, which was accompanied by an increase of ubiquitinated proteins. Interestingly, the proteasomal activities chymotrypsin and caspase-like were decreased whereas trypsin-like activity was maintained. In conclusion, this study revealed the involvement of ubiquitin-proteasome system (UPS) in RHF. Three deregulated mechanisms were discovered: (1) decreased gene and protein expressions of proteasome subunits, (2) decreased specific activity of proteasome; and (3) a specific accumulation of ubiquitinated proteins. This modulation of UPS of RV may provide a novel therapeutic avenue for restoration of cardiac function in the diseased RHF.

Effect of propofol and etomidate on normoxic and chronically hypoxic pulmonary artery.

BACKGROUND: Chronic alveolar hypoxia results in sustained arterial constriction, and increase in pulmonary vascular resistance leading to pulmonary artery hypertension (PAHT). The aim of this study was to investigate the effect of propofol and etomidate on pulmonary artery (PA) reactivity in chronically hypoxic (CH) rats, a model of pulmonary arterial hypertension (PAHT), in normoxic animals, and human PA. METHODS: CH rats were maintained 14 days at 380 mmHg pressure in a hypobaric chamber. Human tissue was retrieved from histological lung pieces from patients undergoing resection for carcinoma. Cumulative concentrations of anaesthetics were tested on isolated vascular rings precontracted with phenylephrine (PHE) or 100 mM KCl. Statistical comparisons were done by ANOVA, followed, when needed, by Student t tests with Bonferroni correction as post-hoc tests. RESULTS: In normoxic rat PA, maximal relaxation (Rmax) induced by etomidate and propofol was 101.3 +/- 0.8% and 94.0 +/- 2.3%, respectively, in KCl-precontracted rings, and 63.3 +/- 9.7% and 46.1 +/- 9.1%, respectively, in PHE-precontracted rings (n = 7). In KCl-precontracted human PA, Rmax was 84.7 +/- 8.6 % and 66.5 +/- 11.8%, for etomidate and propofol, respectively, and 154.2 +/- 22.4 % and 51.6 +/- 15.1 %, respectively, in PHE-precontracted human PA (n = 7). In CH rat PA, the relaxant effect of both anaesthetics was increased in PHE-precontracted and, for etomidate only, in KCl-precontracted PA. In aorta, CH induced no change in the relaxant effect of anaesthetics. CONCLUSION: Propofol and etomidate have relaxant properties in PA from human and normoxic rat. The relaxant effect is specifically accentuated in PA from CH rat, mainly via an effect on the pharmacomechanical coupling. Etomidate appears to be more efficient than propofol at identical concentration, but, taking into account clinical concentrations, etomidate is less potent than propofol, which effect was in the range of clinical doses. Although these findings provide experimental support for the preferential use of etomidate for haemodynamic stability in patients suffering from PAHT, the clinical relevance of the observations requires further investigation.

Effect of short-term organoid culture on the pharmaco-mechanical properties of rat extra- and intrapulmonary arteries.

1 Organoid cultured explants from differentiated tissues have gained renewed interest in the undertaking of physiological and pharmacological studies. In the work herein, we examined the pharmaco-mechanical properties of an in vitro model consisting of organoid cultured rings derived from rat extra- and intrapulmonary arteries, over a period of 4 days in culture. 2 Mechanical changes were quantified using isometric tension measurements on both fresh and cultured pulmonary arterial tissues, with experiments performed in the presence or absence of 10% foetal calf serum. Conventional histochemical and immunofluorescent stainings were also performed to assess tissue structure integrity and apoptosis. 3 The explants developed spontaneous rhythmic contractions (SRC) in approximately half of the vessels. SRC amplitude and time course were modified by conditions and agents acting on membrane potential (high-potassium solutions--levcromakalim, a potassium channel opener), while nitrendipine, an L-type calcium channel blocker, suppressed SRC. 4 Cultured explants also developed a hyper-reactivity to high potassium challenges (10-40 mM). Whereas contraction to serotonin (5-HT) was enhanced in intrapulmonary arteries, contraction to endothelin-1 remained unchanged after 4 days of culture. Serum did not alter contractile properties during the culture period. 5 Endothelial-dependent relaxation was maintained in response to A23187 500 microM, but was abolished in response to 10 microM carbamylcholine. 6 Histological and immuno-histological analyses revealed the absence of hypertrophied vascular wall or apoptosis. 7 In conclusion, the contractile phenotype as well as tissue structure integrity of organoid explants remain essentially intact during short-term culture, making this model suitable for pharmaco-genomic studies.