Journalartikel

Jahr der Veröffentlichung: 2021

Seiten: 100-114

Zeitschrift: American Journal of Respiratory Cell and Molecular Biology

Bandnummer: 64

Heftnummer: 1

ISSN: 1044-1549

eISSN: 1535-4989

DOI Link: https://doi.org/10.1165/rcmb.2019-0431OC

Verlag: American Thoracic Society

Abstract: 
In pulmonary arterial hypertension (PAH), progressive structural remodeling accounts for the pulmonary vasculopathy including the obliteration of the lung vasculature that causes an increase in vascular resistance and mean blood pressure in the pulmonary arteries ultimately leading to right heart failure-mediated death. Deciphering themolecular details of aberrant signaling of pulmonary vascular cells in PAH is fundamental for the development of new therapeutic strategies. We aimed to identify kinases as new potential drug targets that are dysregulated in PAH by means of a peptide-based kinase activity assay. We performed a tyrosine kinase-dependent phosphorylation assay using 144 selected microarrayed substrate peptides. The differential signature of phosphopeptides was used to predict alterations in tyrosine kinase activities in human pulmonary arterialsmoothmuscle cells (HPASMCs) frompatients with idiopathic PAH (IPAH) compared with healthy control cells. Thereby, we observed an overactivation and an increased expression of Jak2 (Janus kinase 2) in HPASMCs from patients with IPAH as compared with controls. In vitro, IL-6-induced proliferation and migration of HPASMCs from healthy individuals as well as from patients with IPAHwere reduced in a dose-dependent manner by theU.S. Food and Drug Administration-approved Jak1 and Jak2 inhibitor ruxolitinib. In vivo, ruxolitinib therapy in two experimental models of pulmonary arterial hypertension dose-dependently attenuated the elevation in pulmonary arterial pressure, partially reduced right ventricular hypertrophy, and almost completely restored cardiac index without signs of adverse events on cardiac function. Therefore, we propose that ruxolitinib may present a novel therapeutic option for patients with PAH by reducing pulmonary vascular remodeling through effectively blocking Jak2-Stat3 (signal transducer of activators of transcription)-mediated signaling pathways.

Harvard-Zitierstil: Yerabolu, D., Weiss, A., Kojonazarov, B., Boehm, M., Schlueter, B., Ruppert, C., et al. (2021) Targeting Jak-Stat Signaling in Experimental Pulmonary Hypertension, American Journal of Respiratory Cell and Molecular Biology, 64(1), pp. 100-114. https://doi.org/10.1165/rcmb.2019-0431OC

APA-Zitierstil: Yerabolu, D., Weiss, A., Kojonazarov, B., Boehm, M., Schlueter, B., Ruppert, C., Gunther, A., Jonigk, D., Grimminger, F., Ghofrani, H., Seeger, W., Weissmann, N., & Schermuly, R. (2021). Targeting Jak-Stat Signaling in Experimental Pulmonary Hypertension. American Journal of Respiratory Cell and Molecular Biology. 64(1), 100-114. https://doi.org/10.1165/rcmb.2019-0431OC