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Growing evidence supports a role for viral and cell\u2010derived double\u2010stranded (ds)\u2010RNA in cardiovascular pathophysiology. Poly(I:C), a dsRNA surrogate, has been shown to induce inflammation, type I interferon (IFN) responses, and osteogenesis through Toll\u2010like receptor 3 in aortic valve interstitial cells (VIC). Here, we aimed to determine whether IFN signaling via Janus kinase (JAK)\/Signal transducers and activators of transcription (STAT) mediates dsRNA\u2010induced responses in primary human VIC. Western blot, ELISA, qPCR, calcification, flow cytometry, and enzymatic assays were performed to evaluate the mechanisms of dsRNA\u2010induced inflammation and calcification. Poly(I:C) triggered a type I IFN response characterized by IFN\u2010regulatory factors gene upregulation, IFN\u2010\u03b2 secretion, and STAT1 activation. Additionally, Poly(I:C) promoted VIC inflammation via NF\u2010\u03baB and subsequent adhesion molecule expression, and cytokine secretion. Pretreatment with ruxolitinib, a clinically used JAK inhibitor, abrogated these responses. Moreover, Poly(I:C) promoted a pro\u2010osteogenic phenotype and increased VIC calcification to a higher extent in cells from males. Inhibition of JAK with ruxolitinib or a type I IFN receptor blocking antibody blunted Poly(I:C)\u2010induced calcification. Mechanistically, Poly(I:C) promoted VIC apoptosis in calcification medium, which was inhibited by ruxolitinib. Moreover, Poly(I:C) co\u2010operated with IFN\u2010\u03b3 to increase VIC calcification by synergistically activating extracellular signal\u2010regulated kinases and hypoxia\u2010inducible factor\u20101\u03b1 pathways. In conclusion, JAK\/STAT signaling mediates dsRNA\u2010triggered inflammation, apoptosis, and calcification and may contribute to a positive autocrine loop in human VIC in the presence of IFN\u2010\u03b3. Blockade of dsRNA responses with JAK inhibitors may be a promising therapeutic avenue for CAVD.<\/jats:p>","DOI":"10.1111\/febs.16026","type":"journal-article","created":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T15:52:07Z","timestamp":1621439527000},"page":"6528-6542","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Clinically used JAK inhibitor blunts dsRNA\u2010induced inflammation and calcification in aortic valve interstitial cells"],"prefix":"10.1111","volume":"288","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8831-1115","authenticated-orcid":false,"given":"Iv\u00e1n","family":"Parra\u2010Izquierdo","sequence":"first","affiliation":[{"name":"Unidad de Excelencia Instituto de Biolog\u00eda y Gen\u00e9tica Molecular CSIC\u2010Universidad de Valladolid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"S\u00e1nchez\u2010Bayuela","sequence":"additional","affiliation":[{"name":"Unidad de Excelencia Instituto de Biolog\u00eda y Gen\u00e9tica Molecular CSIC\u2010Universidad de Valladolid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Casta\u00f1os\u2010Mollor","sequence":"additional","affiliation":[{"name":"Unidad de Excelencia Instituto de Biolog\u00eda y Gen\u00e9tica Molecular CSIC\u2010Universidad de Valladolid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9811-9872","authenticated-orcid":false,"given":"Javier","family":"L\u00f3pez","sequence":"additional","affiliation":[{"name":"ICICOR, Hospital Cl\u00ednico Universitario Valladolid Spain"},{"name":"CIBER de Enfermedades Cardiovasculares (CIBERCV) Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"G\u00f3mez","sequence":"additional","affiliation":[{"name":"Unidad de Excelencia Instituto de Biolog\u00eda y Gen\u00e9tica Molecular CSIC\u2010Universidad de Valladolid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0764-0839","authenticated-orcid":false,"given":"J. 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