Beneficial effects of a preventive treatment with anethole trithione on pulmonary hypertension

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Pulmonary hypertension (PH) is a multifactorial disease characterized by pulmonary arteries (PA) and right ventricular (RV) alterations. Mitochondria dysfunction and associated reactive oxygen species production were shown to contribute to these phenomena. OP2 Drugs start-up demonstrated that anethole trithione (ATT), the active ingredient of its principal lead OP2113, specifically inhibits mitochondrial ROS production from complex I. In this context, this study aims to assess the effects of ATT on PH set-up. By using osmotic mini-pump, influence of a preventive treatment with ATT or its vehicle was tested on PH development in male rats exposed to three weeks of chronic hypoxia (CH - 10 % O2). PA and cardiac PH hallmarks (remodelling, fibrosis and hemodynamic parameters) were assessed. Contraction and intracellular calcium signal of isolated cardiomyocytes from RV were simultaneously measured by IonOptix system. We quantified cardiac mitochondrial mass by measuring VDAC1 expression by western blotting. The effect of preventive or acute treatment with ATT on PA reactivity was measured by isometric tension. In rats with PH, preventive treatment with ATT reduced PA remodelling and RV systolic pressure, whereas RV hypertrophy and fibrosis seemed not to be affected. However, this preventive treatment abolished the decrease of both speed of cardiomyocytes contraction and VDAC1 expression induced by CH. Preventive and acute treatment with ATT reversed PA hyperreactivity to 5-HT in rats with PH. Acute ATT treatment triggered a sustained relaxation of preconstricted PA in both control and PH conditions. L-NAME (eNOS inhibitor) and CHAPS (non-denaturing detergent used to remove endothelium) did not affect the acute effect of ATT on PA contraction and relaxation whereas glibenclamide (KATP channel inhibitor) attenuated ATT induced relaxation. Y27632 (a ROCK inhibitor) and ATT induced additive reduction of 5-HT contraction. Altogether, these results highlighted the benefit of an ATT preventive treatment on PA reactivity and remodelling as well as RV cardiac function suggesting a potential therapeutic interest of ATT in PH set-up. Whereas ATT effect on reactivity seemed to be endothelium and ROCK-independent, KATP channel was partly involved in ATT-induced relaxation.