{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:38:35Z","timestamp":1790717915091,"version":"4.1.0"},"reference-count":66,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T00:00:00Z","timestamp":1753747200000},"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":[[2025,7,29]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      The role of cardiac CD (cluster of differentiation) 206\n                      <jats:sup>+<\/jats:sup>\n                      macrophages in chronic heart failure (HF) is unknown. We examined whether CD206\n                      <jats:sup>+<\/jats:sup>\n                      macrophages expressing IL (interleukin)\u20134R\u03b1 are key drivers of adverse left ventricular (LV) remodeling in HF.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>Adult C57BL\/6 mice underwent nonreperfused myocardial infarction to induce HF. Macrophages in murine and human hearts were profiled using flow cytometry and immunostaining. In vivo myeloid-specific IL-4R\u03b1 deletion and intramyocardial macrophage adoptive transfer defined the functional effects of macrophages polarized by IL-4 (M[IL-4]). Antisense oligonucleotides were used for in vivo IL-4R\u03b1 gene silencing in mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      CD206\n                      <jats:sup>+<\/jats:sup>\n                      macrophages steadily expanded in hearts after myocardial infarction, such that at 8 weeks after myocardial infarction, they comprised \u224885% of all macrophages. These macrophages were proliferative, predominantly CCR2\n                      <jats:sup>\u2013<\/jats:sup>\n                      (C-C motif chemokine receptor) and MHC (major histocompatibility complex) II\n                      <jats:sup>hi<\/jats:sup>\n                      , and correlated with LV dysfunction and fibrosis. Nearly half of CD206\n                      <jats:sup>+<\/jats:sup>\n                      macrophages expressed IL-4R\u03b1, and the majority of CD206\n                      <jats:sup>+<\/jats:sup>\n                      IL-4R\u03b1\n                      <jats:sup>+<\/jats:sup>\n                      macrophages coexpressed profibrotic FIZZ (found in inflammatory zone) 1. Bone marrow\u2013derived CD206\n                      <jats:sup>+<\/jats:sup>\n                      M[IL-4] macrophages also exhibited marked upregulation of FIZZ1 and induced FIZZ1-dependent myofibroblast differentiation of both cardiac mesenchymal stem cells and cardiac fibroblasts, in part related to DLL (Delta-like ligand)-4\/Jagged1-Notch1 signaling in cardiac mesenchymal stem cells. Intramyocardial adoptive transfer of M[IL-4], but not IL-10-polarized (M[IL-10]), CD206\n                      <jats:sup>+<\/jats:sup>\n                      macrophages to na\u00efve mice induced progressive LV remodeling over 4 weeks, increasing fibrosis, cardiomyocyte hypertrophy, and apoptosis. Myeloid-specific IL-4R\u03b1 gene deletion in HF (initiated 4 weeks after myocardial infarction) in IL-4R\u03b1\n                      <jats:sup>f\/f<\/jats:sup>\n                      LysM-Cre\n                      <jats:sup>ERT2<\/jats:sup>\n                      mice significantly reduced CD206\n                      <jats:sup>+<\/jats:sup>\n                      macrophage proliferation and effectively depleted CD206\n                      <jats:sup>+<\/jats:sup>\n                      IL-4R\u03b1\n                      <jats:sup>+<\/jats:sup>\n                      cardiac macrophages. This was associated with abrogation of LV remodeling progression, reduction of cardiac fibrosis, and improved neovascularization. In vivo IL-4R\u03b1 gene silencing in mice with established HF effectively depleted cardiac CD206\n                      <jats:sup>+<\/jats:sup>\n                      IL-4R\u03b1\n                      <jats:sup>+<\/jats:sup>\n                      macrophages and reversed LV remodeling, improving fibrosis, neovascularization, and dysfunction, and suppressed both local and systemic inflammation. Last, alternatively activated CD206\n                      <jats:sup>+<\/jats:sup>\n                      and CD163\n                      <jats:sup>+<\/jats:sup>\n                      macrophages were significantly expanded in human failing hearts and correlated with fibrosis. The majority of CD163\n                      <jats:sup>+<\/jats:sup>\n                      macrophages expressed IL-4R\u03b1 and FIZZ3, the human homolog of FIZZ1.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      Cardiac CD206\n                      <jats:sup>+<\/jats:sup>\n                      IL-4R\u03b1\n                      <jats:sup>+<\/jats:sup>\n                      macrophages proliferate and expand in HF and are key mediators of pathological remodeling and fibrosis, in part through the secretion of FIZZ1. Inhibition of CD206\n                      <jats:sup>+<\/jats:sup>\n                      macrophage IL-4R\u03b1 signaling alleviates LV remodeling in ischemic cardiomyopathy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.124.072411","type":"journal-article","created":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T05:00:15Z","timestamp":1746075615000},"page":"257-273","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":25,"title":["CD206\n                    <sup>+<\/sup>\n                    IL-4R\u03b1\n                    <sup>+<\/sup>\n                    Macrophages Are Drivers of Adverse Cardiac Remodeling in Ischemic Cardiomyopathy"],"prefix":"10.1161","volume":"152","author":[{"given":"Qiongxin","family":"Wang","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO (Q.W., M.A.I., Y.Z., G.R., T.H., S.D.P.)."},{"name":"Department of Cardiology, Zhongnan Hospital of Wuhan University, China (Q.W.)."},{"name":"Department of Medicine (Cardiovascular Disease), University of Alabama at Birmingham (Q.W., M.A.I., Y.Z., G.R., T.H., G.Z., S.M.P., S.D.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7452-6123","authenticated-orcid":true,"given":"Mohamed Ameen","family":"Ismahil","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO (Q.W., M.A.I., Y.Z., G.R., T.H., S.D.P.)."},{"name":"Department of Medicine (Cardiovascular Disease), University of Alabama at Birmingham (Q.W., M.A.I., Y.Z., G.R., T.H., G.Z., S.M.P., S.D.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Zhu","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Washington University 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