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

TY - JOUR

T1 - Myeloperoxidase aggravates pulmonary arterial hypertension by activation of vascular Rho-kinase

AU - Klinke, Anna

AU - Berghausen, Eva

AU - Friedrichs, Kai

AU - Molz, Simon

AU - Lau, Denise

AU - Remane, Lisa

AU - Berlin, Matthias

AU - Kaltwasser, Charlotte

AU - Adam, Matti

AU - Mehrkens, Dennis

AU - Mollenhauer, Martin

AU - Manchanda, Kashish

AU - Ravekes, Thorben

AU - Heresi, Gustavo A

AU - Aytekin, Metin

AU - Dweik, Raed A

AU - Hennigs, Jan K

AU - Kubala, Lukas

AU - Michaëlsson, Erik

AU - Rosenkranz, Stephan

AU - Rudolph, Tanja K

AU - Hazen, Stanley L

AU - Klose, Hans

AU - Schermuly, Ralph T

AU - Rudolph, Volker

AU - Baldus, Stephan

PY - 2018/6/7

Y1 - 2018/6/7

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1172/jci.insight.97530

DO - 10.1172/jci.insight.97530

M3 - SCORING: Journal article

C2 - 29875311

VL - 3

JO - JCI INSIGHT

JF - JCI INSIGHT

SN - 2379-3708

IS - 11

ER -