Pulmonary arterial hypertension (PAH) is characterized by an excessive vascular remodeling, which accounts for the obliteration of the lung vasculature resulting an increase in vascular resistance and mean blood pressure in the pulmonary arteries ultimately leading to right heart failure and death. Vascular remodeling involves increased proliferation of cells in all three layers of the vessels; intimal-endothelial, medial-smooth muscle and adventitial-fibroblast cells. Deciphering the molecular details of aberrant signaling in pulmonary vascular cells in P(A)H is fundamental for the development of new therapeutic strategies. I aimed to identify tyrosine kinases as new potential drug targets that are dysregulated in PAH by means of a peptide-based kinase activity assay. I performed a tyrosine kinase dependent phosphorylation assay using 144 selected microarrayed kinase substrate peptides. The differential signature of phospho-peptides was used to predict alterations in tyrosine kinase activities in pulmonary arterial smooth muscle cells (HPASMCs) from IPAH patients compared to healthy control cells. Thereby, i observed an over-activation and an increased expression of Janus kinase 2 (Jak2) in HPASMCs from IPAH patients. In line with this finding, increased expression of Jak2 and it s downstream target Stat3 was observed in HPASMCs from IPAH patients as compared to donors. Furthermore, similar upregulation was observed in lung homogenates from MCT rats as compared to healthy rats.I demonstrated a decrease in proliferation and migration of HPASMCs from healthy individuals as well as from IPAH patients upon exposure to the FDA-approved Jak2-inhibitor ruxolitinib. In vivo experiments were performed in two established experimental models of pulmonary hypertension MCT rats and chronic hypoxia mice. I demonstrated, ruxolitinib dose-dependently attenuated elevated pulmonary arterial pressure, reduced right heart hypertrophy and restored cardiac index in hypoxia-induced PH in mice and monocrotaline-induced PAH in rats. No adverse events of ruxolitinib on cardiac function could be detected. These results suggest that ruxolitinib is a novel therapeutic agent in PAH by effectively blocking Jak2-Stat3 mediated signaling pathways.
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