Klinke, Anna, Berghausen, Eva, Friedrichs, Kai, Molz, Simon, Lau, Denise, Remane, Lisa, Berlin, Matthias, Kaltwasser, Charlotte, Adam, Matti ORCID: 0000-0002-6990-8135, Mehrkens, Dennis ORCID: 0000-0002-8578-0290, Mollenhauer, Martin, Manchanda, Kashish, Ravekes, Thorben, Heresi, Gustavo A., Aytekin, Metin, Dweik, Raed A., Hennigs, Jan K. ORCID: 0000-0002-7784-8267, Kubala, Lukas ORCID: 0000-0002-7729-7338, Michaelsson, Erik, Rosenkranz, Stephan, Rudolph, Tanja K., Hazen, Stanley L., Klose, Hans, Schermuly, Ralph T., Rudolph, Volker and Baldus, Stephan (2018). Myeloperoxidase aggravates pulmonary arterial hypertension by activation of vascular Rho-kinase. JCI Insight, 3 (11). ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 2379-3708

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Klinke, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berghausen, EvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Friedrichs, KaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Molz, SimonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lau, DeniseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Remane, LisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berlin, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaltwasser, CharlotteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Adam, MattiUNSPECIFIEDorcid.org/0000-0002-6990-8135UNSPECIFIED
Mehrkens, DennisUNSPECIFIEDorcid.org/0000-0002-8578-0290UNSPECIFIED
Mollenhauer, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Manchanda, KashishUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ravekes, ThorbenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heresi, Gustavo A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aytekin, MetinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dweik, Raed A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hennigs, Jan K.UNSPECIFIEDorcid.org/0000-0002-7784-8267UNSPECIFIED
Kubala, LukasUNSPECIFIEDorcid.org/0000-0002-7729-7338UNSPECIFIED
Michaelsson, ErikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosenkranz, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rudolph, Tanja K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hazen, Stanley L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klose, HansUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schermuly, Ralph T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rudolph, VolkerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baldus, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-182978
DOI: 10.1172/jci.insight.97530
Journal or Publication Title: JCI Insight
Volume: 3
Number: 11
Date: 2018
Publisher: AMER SOC CLINICAL INVESTIGATION INC
Place of Publication: ANN ARBOR
ISSN: 2379-3708
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NITRIC-OXIDE; PROTEIN; VASOCONSTRICTION; EXPRESSION; RISKMultiple languages
Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/18297

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