{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T20:31:53Z","timestamp":1783542713275,"version":"3.55.0"},"reference-count":57,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>Inflammation and metabolic reprogramming are hallmarks of cardiovascular disorders, wherein myocardiocytes switch from fatty acids to glucose to yield energy. This has also been found in the myocardium of patients with calcific aortic valve disease, a prevalent disease exhibiting features of inflammatory disease that lacks pharmacological treatments. Therefore, we posited that the analysis of proinflammatory and metabolic mechanisms might give cues to disclose therapeutic targets.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>The metabolic analysis of aortic valve interstitial cells (VIC) explanted from human valves was performed by Seahorse real-time cell metabolic analysis, fluxomics using ultra-performance liquid chromatography\/mass spectrometry, quantitative polymerase chain reaction, metabolite quantitation, and loss-of-function experiments with gene silencing and pharmacological approaches. Findings were validated in quiescent VIC, 3-dimensional porcine VIC\u2013valve endothelial cell cocultures, as well as in valve leaflets and VIC from human patients.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>The hyperglycolytic program present in calcific aortic valve disease was replicated in control\/nonstenotic VIC by cytokine exposure and enhanced by pathogen-associated molecular patterns. Inflammatory stimuli increased fluxes in glycolysis, tricarboxylic acid cycle, and the pentose phosphate pathway. Inflamed VIC exhibited increased glycolytic ATP production and lactate secretion, as well as changes in redox state and metabolic gene profile, that is, upregulation of glycolytic enzyme expression and downregulation of G6PD (glucose-6-phosphate dehydrogenase), the rate-limiting enzyme of the oxidative phase of pentose phosphate pathway. Notably, these alterations were replicated in quiescent VIC and 3-dimensional VIC\u2013valve endothelial cell cocultures and are observed in diseased valves from patients. Strikingly, metabolic rewiring in control VIC was required for inflammation-triggered calcification and differentiation. A Food and Drug Administration\u2013approved JAK (Janus kinase) inhibitor blunted these changes, whose major drivers are the JAK-STAT (signal transducer and activator of transcription) system, HIF (hypoxia-inducible factor)-1\u03b1, and NF-\u03baB (nuclear factor-\u03baB).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>Inflammation reprograms VIC metabolism to support calcification by downregulating oxidative phase of pentose phosphate pathway and enhancing glycolytic flux and oxidative stress. These findings parallel the metabolic profile of stenotic VIC and provide novel therapeutic clues.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.124.322375","type":"journal-article","created":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T09:00:17Z","timestamp":1746090017000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":13,"title":["Inflammation via JAK-STAT\/HIF-1\u03b1 Drives Metabolic Changes in Pentose Phosphate Pathway and Glycolysis That Support Aortic Valve Cell Calcification"],"prefix":"10.1161","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4773-7037","authenticated-orcid":true,"given":"Tania","family":"S\u00e1nchez-Bayuela","sequence":"first","affiliation":[{"name":"Unidad de Excelencia Instituto de Biomedicina y Gen\u00e9tica Molecular de Valladolid (IBGM), Universidad de Valladolid y Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Spain (T.S.-B., M.P.-R., I.P.-I., C.G., O.M., E.P.-R., M.S.C., C.G.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4649-7354","authenticated-orcid":true,"given":"Mirian","family":"Peral-Rodrigo","sequence":"additional","affiliation":[{"name":"Unidad de Excelencia Instituto de Biomedicina y Gen\u00e9tica Molecular de Valladolid (IBGM), Universidad de Valladolid y Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Spain (T.S.-B., M.P.-R., I.P.-I., C.G., O.M., E.P.-R., M.S.C., C.G.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8831-1115","authenticated-orcid":true,"given":"Iv\u00e1n","family":"Parra-Izquierdo","sequence":"additional","affiliation":[{"name":"Unidad de Excelencia Instituto de Biomedicina y Gen\u00e9tica Molecular de Valladolid (IBGM), Universidad de Valladolid y Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Spain (T.S.-B., M.P.-R., I.P.-I., C.G., O.M., E.P.-R., M.S.C., C.G.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6193-629X","authenticated-orcid":true,"given":"Javier","family":"L\u00f3pez","sequence":"additional","affiliation":[{"name":"ICICOR, Hospital Cl\u00ednico Universitario, Valladolid, Spain (J.L., J.A.S.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2121-6616","authenticated-orcid":true,"given":"Cristina","family":"G\u00f3mez","sequence":"additional","affiliation":[{"name":"Unidad de Excelencia Instituto de Biomedicina y Gen\u00e9tica Molecular de Valladolid (IBGM), Universidad de Valladolid y Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Spain (T.S.-B., M.P.-R., I.P.-I., C.G., O.M., E.P.-R., M.S.C., C.G.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0241-8756","authenticated-orcid":true,"given":"Olimpio","family":"Montero","sequence":"additional","affiliation":[{"name":"Unidad de Excelencia Instituto de Biomedicina y Gen\u00e9tica Molecular de Valladolid (IBGM), Universidad de Valladolid y Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Spain (T.S.-B., M.P.-R., I.P.-I., C.G., O.M., E.P.-R., M.S.C., C.G.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3658-6803","authenticated-orcid":true,"given":"Enrique","family":"P\u00e9rez-Riesgo","sequence":"additional","affiliation":[{"name":"Unidad de Excelencia Instituto de Biomedicina y Gen\u00e9tica Molecular de Valladolid (IBGM), Universidad de Valladolid y Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Spain (T.S.-B., M.P.-R., I.P.-I., C.G., O.M., E.P.-R., M.S.C., C.G.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0764-0839","authenticated-orcid":true,"given":"J. 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