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Myeloperoxidase aggravates pulmonary arterial hypertension by activation of vascular Rho-kinase
Anna Klinke, … , Volker Rudolph, Stephan Baldus
Anna Klinke, … , Volker Rudolph, Stephan Baldus
Published June 7, 2018
Citation Information: JCI Insight. 2018;3(11):e97530. https://doi.org/10.1172/jci.insight.97530.
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Research Article Cardiology Inflammation

Myeloperoxidase aggravates pulmonary arterial hypertension by activation of vascular Rho-kinase

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Abstract

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.

Authors

Anna Klinke, Eva Berghausen, Kai Friedrichs, Simon Molz, Denise Lau, Lisa Remane, Matthias Berlin, Charlotte Kaltwasser, Matti Adam, Dennis Mehrkens, Martin Mollenhauer, Kashish Manchanda, Thorben Ravekes, Gustavo A. Heresi, Metin Aytekin, Raed A. Dweik, Jan K. Hennigs, Lukas Kubala, Erik Michaëlsson, Stephan Rosenkranz, Tanja K. Rudolph, Stanley L. Hazen, Hans Klose, Ralph T. Schermuly, Volker Rudolph, Stephan Baldus

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Figure 1

Myeloperoxidase in patients with pulmonary arterial hypertension.

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Myeloperoxidase in patients with pulmonary arterial hypertension.
Myelop...
Myeloperoxidase (MPO) accumulates in plasma and lung tissue of patients with pulmonary arterial hypertension (PAH) and is related to increased mortality. (A) Immunohistochemical staining of MPO in lung sections of control subjects and patients with pulmonary hypertension (PH). Representative images of 3 separate individuals per group are displayed. Scale bar: 50 μm. (B) MPO plasma levels in PAH patients at baseline. n = 95; *P < 0.01. Data represent median, with interquartile range and whiskers indicating 5th to 95th percentile. Statistical analysis was performed by Mann-Whitney U test. (C) Kaplan-Meier analysis of survival of PAH patients with MPO plasma levels <583 pmol/l (low) or >583 pmol/l (high). n = 95; χ2 = 5.134, P < 0.05. Statistical analysis was performed by log-rank test.

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