Pulmonary arterial hypertension (PAH) remains a disease with limited therapeutic options and dismal prognosis. Despite its etiologic heterogeneity, the underlying unifying pathophysiology is characterized by increased vascular tone and adverse remodeling of the pulmonary circulation. Myeloperoxidase (MPO), an enzyme abundantly expressed in neutrophils, has potent vasoconstrictive and profibrotic properties, thus qualifying as a potential contributor to this disease. Here, we sought to investigate whether MPO is causally linked to the pathophysiology of PAH. Investigation of 2 independent clinical cohorts revealed that MPO plasma levels were elevated in subjects with PAH and predicted adverse outcome. Experimental analyses showed that, upon hypoxia, right ventricular pressure was less increased in Mpo-/- than in WT mice. The hypoxia-induced activation of the Rho-kinase pathway, a critical subcellular signaling pathway yielding vasoconstriction and structural vascular remodeling, was blunted in Mpo-/- mice. Mice subjected to i.v. infusion of MPO revealed activation of Rho-kinase and increased right ventricular pressure, which was prevented by coinfusion of the Rho-kinase inhibitor Y-27632. In the Sugen5416/hypoxia rat model, PAH was attenuated by the MPO inhibitor AZM198. The current data demonstrate a tight mechanistic link between MPO, the activation of Rho-kinase, and adverse pulmonary vascular function, thus pointing toward a potentially novel avenue of treatment.

Bioscience Heart Failure Cardiovascular Renal and Metabolism Innovative Medicines and Early Development Biotech Unit AstraZeneca Gothenburg Sweden

Cardiovascular Institute Stanford University School of Medicine Stanford California USA

Center for Molecular Medicine Cologne CMMC University of Cologne Cologne Germany

Department of Cellular and Molecular Medicine Cleveland Clinic Cleveland Ohio USA

Department of Pneumology University Medical Center Hamburg Eppendorf Hamburg Germany

Heart Center Department of Cardiology

Institute of Biophysics Czech Academy of Sciences Brno Czech Republic

International Clinical Research Center Centre of Biomolecular and Cellular Engineering St Anne's University Hospital Brno Brno Czech Republic

Pathobiology Lerner Research Institute Cleveland Clinic Cleveland Ohio USA

Pulmonary and Critical Care Medicine Respiratory Institute and

Universities of Giessen and Marburg Lung Center Member of the German Center for Lung Research Giessen Germany

University Heart Center Hamburg University Medical Center Hamburg Eppendorf Hamburg Germany

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