Peroxiredoxin 2 Plays a Pivotal Role Against Oxidation in the Early Phase of Pulmonary Artery Hypertension

Background. Peroxiredoxin 2 (Prx2) is a typical 2-cysteine (Cys) peroxiredoxin ubiquitously expressed. Prx2 is able to efficiently scavenge H2O2 and other hydro-peroxides to maintain intracellular redox balance. Prx2 has been largely studied in red cells, where it acts as antioxidant system and chaperone-like molecule. Although growing evidences indicate the important role of Prx2 in different cell models, much still remains to be investigated in complex disease scenario such as chronic lung disease or stress erythropoiesis. Aim. The major aim of my work is to understand the functional role of Peroxiredoxin 2 in a mouse model of pulmonary artery hypertension. Section 1. I focus on the functional role of peroxiredoxin-2 (Prx2) in lung homeostasis. Here, I studied the events related to the generation of pulmonary artery hypertension (PAH), a life threatening and highly invalidating chronic disorder. Hypoxia was used as trigger factor. I found that Prx2-/- mice displayed chronic lung inflammatory disease associated with (i) abnormal pulmonary vascular dysfunction; and (ii) increased markers of extracellular-matrix remodelling. Rescue experiments with in vivo the administration of fused-recombinant-PEP-Prx2 to hypoxic mice show a reduction in pulmonary inflammatory vasculopathy and down-regulation of autophagy. Thus, we propose Prx2 plays a pivotal role in the early stage of PAH as multimodal anti-oxidant system targeting oxidation, inflammatory vasculopathy and indirectly autophagy. Section 2. I have studied the effect of iron-overload (IO) diet on Prx2-/- mouse erythropoiesis and its link with iron homeostasis. In Prx2-/- mice, IO displayed a potent cytotoxic effect on erythropoiesis and it was associated with lacking in liver STAT3 activation. This results in low hepcidin expression. Treatment with PEP Prx2 ameliorates IO-induced anemia and restored liver STAT3 activation, with adequate hepcidin expression in relation to IO. The importance of Prx2 on the axis between erythropoiesis and iron metabolism is also supported by the beneficial effects of PEP Prx2 on hepcidin levels a mouse model of β-thalassemia. Section 3. I have studied a humanized mouse model for sickle cell disease (SCD, Tim Townes mouse model). Based on the revision of the literature, SCD and healthy mice were supplemented with ω-3 fatty acids. Hypoxia/reoxygenation stress was used to mimic SCD acute vaso-occlusive crisis. We found that ω-3 fatty supplementation reduces: (i) sickle cell related oxidative stress, (ii) systemic and local (lung and liver) inflammatory response, (iii) vascular endothelial activation and (iv) vascular dysfunction. Our data generate a rationale for ω-3 fatty supplementation in clinical management of SCD patients.