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Τετάρτη 30 Αυγούστου 2017

Peroxiredoxin-2 plays a pivotal role as multimodal cytoprotector in the early phase of pulmonary hypertension

Publication date: November 2017
Source:Free Radical Biology and Medicine, Volume 112
Author(s): Enrica Federti, Alessandro Matté, Alessandra Ghigo, Immacolata Andolfo, Cimino James, Angela Siciliano, Christophe Leboeuf, Anne Janin, Francesco Manna, Soo Young Choi, Achille Iolascon, Elisabetta Beneduce, Davide Melisi, Dae Won Kim, Sonia Levi, Lucia De Franceschi
Pulmonary-artery-hypertension (PAH) is a life-threatening and highly invalidating chronic disorder. Chronic oxidation contributes to lung damage and disease progression. Peroxiredoxin-2 (Prx2) is a typical 2-cysteine (Cys) peroxiredoxin but its role on lung homeostasis is yet to be fully defined. Here, we showed that Prx2-/- mice displayed chronic lung inflammatory disease associated with (i) abnormal pulmonary vascular dysfunction; and (ii) increased markers of extracellular-matrix remodeling. Hypoxia was used to induce PAH. We focused on the early phase PAH to dissect the role of Prx2 in generation of PAH. Hypoxic Prx2-/-mice showed (i) amplified inflammatory response combined with cytokine storm; (ii) vascular activation and dysfunction; (iii) increased PDGF-B lung levels, as marker of extracellular-matrix deposition and remodeling; and (iv) ER stress with activation of UPR system and autophagy. Rescue experiments with in vivo the administration of fused-recombinant-PEP-Prx2 show a reduction in pulmonary inflammatory vasculopathy and in ER stress with down-regulation of autophagy. Thus, we propose Prx2 plays a pivotal role in the early stage of PAH as multimodal cytoprotector, targeting oxidation, inflammatory vasculopathy and ER stress with inhibition of autophagy. Collectively, our data indicate that Prx2 is able to interrupt the hypoxia induced vicious cycle involving oxidation-inflammation-autophagy in the pathogenesis of PAH.

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