Clinically used JAK inhibitor blunts dsRNA‐induced inflammation and calcification in aortic valve interstitial cells
نویسندگان
چکیده
Calcific aortic valve disease (CAVD) is the most prevalent valvulopathy worldwide. Growing evidence supports a role for viral and cell-derived double-stranded (ds)-RNA in cardiovascular pathophysiology. Poly(I:C), dsRNA surrogate, has been shown to induce inflammation, type I interferon (IFN) responses, osteogenesis through Toll-like receptor 3 interstitial cells (VIC). Here, we aimed determine whether IFN signaling via Janus kinase (JAK)/Signal transducers activators of transcription (STAT) mediates dsRNA-induced responses primary human VIC. Western blot, ELISA, qPCR, calcification, flow cytometry, enzymatic assays were performed evaluate mechanisms inflammation calcification. Poly(I:C) triggered response characterized by IFN-regulatory factors gene upregulation, IFN-β secretion, STAT1 activation. Additionally, promoted VIC NF-κB subsequent adhesion molecule expression, cytokine secretion. Pretreatment with ruxolitinib, clinically used JAK inhibitor, abrogated these responses. Moreover, pro-osteogenic phenotype increased calcification higher extent from males. Inhibition ruxolitinib or blocking antibody blunted Poly(I:C)-induced Mechanistically, apoptosis medium, which was inhibited ruxolitinib. co-operated IFN-γ increase synergistically activating extracellular signal-regulated kinases hypoxia-inducible factor-1α pathways. In conclusion, JAK/STAT dsRNA-triggered apoptosis, may contribute positive autocrine loop presence IFN-γ. Blockade inhibitors be promising therapeutic avenue CAVD.
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ژورنال
عنوان ژورنال: FEBS Journal
سال: 2021
ISSN: ['1742-464X', '1742-4658']
DOI: https://doi.org/10.1111/febs.16026