{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T18:51:28Z","timestamp":1791226288359,"version":"4.1.0"},"reference-count":57,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"14","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Genetic variants in components or regulators of the RAS\u2013mitogen-activated protein kinase (RAS-MAPK) signaling pathway are causative for severe and early-onset hypertrophic cardiomyopathy (HCM) in patients with Noonan syndrome (NS). Despite paracrine communication being considered to play a pivotal role in the etiology of cardiomyopathies, there is a paucity of knowledge about the underlying pathomechanism that leads to the development of HCM and cardiac fibrosis in NS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      To dissect the impact of noncardiomyocytes in the development of NS, we employed two-dimensional and three-dimensional human induced pluripotent stem cell models of\n                      <jats:italic toggle=\"yes\">LZTR1<\/jats:italic>\n                      deficiency alongside induced pluripotent stem cells derived from patients with NS with pathogenic variants in key RAS-MAPK genes and analyzed these cells and tissues at the molecular, cellular, and functional levels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>Our findings revealed that cytokine-mediated cellular crosstalk between cardiac fibroblasts and cardiomyocytes, predominantly activated in the disease state, serves as a primary driver of the disease. Cardiac fibroblast\u2013specific IL-8 (interleukin-8) secretion induced fibrosis-related signatures, tissue stiffness, cardiomyocyte hypertrophy, and hypercontractility, identifying dysregulated IL-8 as a heart-autonomous signaling molecule independent of inflammation and immune cell involvement. Inhibition of IL-8\u2013CXCR1 signaling by reparixin reversed the pathological effects in cardiac fibroblasts and cardiomyocytes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>These data provide evidence that targeting aberrant IL-8\u2013CXCR1 signaling may be an effective therapeutic option for patients with NS-associated HCM.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.125.074155","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T09:00:16Z","timestamp":1776330016000},"page":"1339-1359","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Targeting Interleukin-8\u2013Mediated Cellular Crosstalk Reverses Hypertrophic Cardiomyopathy and Cardiac Fibrosis in Noonan Syndrome"],"prefix":"10.1161","volume":"154","author":[{"given":"Jakob","family":"Fell","sequence":"first","affiliation":[{"name":"Departments of Cardiology and Pneumology (J.F., M.G.P.-G., F.K., A.V.B., A.F., R.H., G.H., L.C.), University Medical Center G\u00f6ttingen, G\u00f6ttingen, Germany."},{"name":"German Center for Cardiovascular Research, partner site Lower Saxony, G\u00f6ttingen, Germany (J.F., M.G.P.-G., F.K., G.K., G.L.S., C.L., A.V.B., S.L., G.H., W.-H.Z., B.W., L.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario G.","family":"Pavez-Giani","sequence":"additional","affiliation":[{"name":"Departments of Cardiology and Pneumology (J.F., M.G.P.-G., F.K., A.V.B., A.F., R.H., G.H., L.C.), University Medical Center G\u00f6ttingen, G\u00f6ttingen, Germany."},{"name":"German Center for Cardiovascular Research, partner site Lower Saxony, G\u00f6ttingen, Germany (J.F., M.G.P.-G., F.K., G.K., G.L.S., C.L., A.V.B., S.L., G.H., W.-H.Z., B.W., 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