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.
- Klíčová slova
- Cardiology, Cardiovascular disease, Inflammation, Innate immunity, Microcirculation,
- MeSH
- amidy aplikace a dávkování MeSH
- arteria pulmonalis patologie patofyziologie MeSH
- dospělí MeSH
- hypoxie krev etiologie patologie MeSH
- intravenózní infuze MeSH
- Kaplanův-Meierův odhad MeSH
- kinázy asociované s Rho antagonisté a inhibitory metabolismus MeSH
- kohortové studie MeSH
- krysa rodu Rattus MeSH
- lidé středního věku MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- peroxidasa aplikace a dávkování krev metabolismus MeSH
- plíce patologie MeSH
- plicní hypertenze krev mortalita patologie patofyziologie MeSH
- potkani Sprague-Dawley MeSH
- pyridiny aplikace a dávkování MeSH
- rekombinantní proteiny aplikace a dávkování krev metabolismus MeSH
- remodelace cév účinky léků fyziologie MeSH
- vazokonstrikce účinky léků fyziologie MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- krysa rodu Rattus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- amidy MeSH
- kinázy asociované s Rho MeSH
- MPO protein, human MeSH Prohlížeč
- peroxidasa MeSH
- pyridiny MeSH
- rekombinantní proteiny MeSH
- Y 27632 MeSH Prohlížeč
