Pulmonary arterial Hypertension (PAH) is a progressive disease which is characterized by the elevated level of mean pulmonary arterial pressure. Increased pulmonary arterial pressure is the consequence of vasoconstriction, pulmonary vascular remodelling and in-situ thrombosis of medium and small size arteries and arterioles (Humbert et al. 2004). The term "vascular remodelling" describes structural changes of vasculature, in particular occlusions or hypertrophy. In normal conditions, there is a balance between proliferation and apoptosis of vascular cells, namely fibroblasts, endothelial cells or, the most relevant for our studies, pulmonary arterial smooth muscle cells (PASMCs). In pulmonary hypertension, the balance is disturbed in favor of proliferation. Janus Kinases, JAK1, JAK2, JAK3 and TYK2, are the family of tyrosine kinases, which mediate cytokine and growth factors signalling. The main downstream target of JAK is STAT, Signal transducers and activators of transcription, the transcription factors (Laurence 2012). After STAT is phosphorylated by JAK, it dimerizes and transclocates to the nucleus, where it interacts with the promoter regions of genes and regulates the transcription. Aberrant activation of the JAK/STAT pathway has been reported in a variety of disease states, including inflammatory conditions, hematologic malignancies, and solid tumors. A series of agents with different specificities against different members of the JAK family of proteins is currently undergoing evaluation in clinical trials for patients with myeloproliferative neoplasms (MPN), lymphoma, solid tumors such as breast or pancreatic cancer. STATs play an important role in cellular functions and it seems there are no exclusive upstream regulators. The cross-interaction between JAK, Src and STATs can explain the downregulation of phospho-STAT3 and STAT5 levels after inhibition of both Src and JAK, as well as comparable effects on PASMC proliferation and migration. It seems that Src and JAK act in concert with each other, maintaining the balance of common downstream targets.In our research we have confirmed the role of PDGF in regulating JAK and Src signal induction. Furthermore we have also demonstrated the interference of canonical JAK/STAT pathway with Src kinase and tight cooperation between JAK, Src and their downstream target STATs. More important, our study has demonstrated a positivetherapeutic effect of JAK1 and JAK2 inhibition by Momelotinib (CYT387). By comparing the result to another JAK inhibitor Pyridone 6 and Src inhibitor PP2, we conclude that targeting JAK decrease the proliferation and migration rates of human PASMCs, which is a therapeutic angle for PAH.
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