{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T23:35:31Z","timestamp":1790379331428,"version":"4.1.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2015,11,6]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Inflammation in post\u2013myocardial infarction (MI) is necessary for myocyte repair and wound healing. Unfortunately, it is also a key component of subsequent heart failure pathology. Transcription factor forkhead box O4 (FoxO4) regulates a variety of biological processes, including inflammation. However, its role in MI remains unknown.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>To test the hypothesis that FoxO4 promotes early post-MI inflammation via endothelial arginase 1 (Arg1).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              We induced MI in wild-type and\n              <jats:italic>FoxO4<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice.\n              <jats:italic>FoxO4<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice had a significantly higher post-MI survival, better cardiac function, and reduced infarct size.\n              <jats:italic>FoxO4<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              hearts had significantly fewer neutrophils, reduced expression of cytokines, and competitive nitric oxide synthase inhibitor Arg1. We generated conditional\n              <jats:italic>FoxO4<\/jats:italic>\n              knockout mice with\n              <jats:italic>FoxO4<\/jats:italic>\n              deleted in cardiac mycoytes or endothelial cells.\n              <jats:italic>FoxO4<\/jats:italic>\n              endothelial cell\u2013specific knockout mice showed significant post-MI improvement of cardiac function and reduction of neutrophil accumulation and cytokine expression, whereas\n              <jats:italic>FoxO4<\/jats:italic>\n              cardiac mycoyte\u2013specific knockout mice had no significant difference in cardiac function and post-MI inflammation from those of control littermates. FoxO4 binds the Foxo-binding site in the Arg1 promoter and activates Arg1 transcription. FoxO4 knockdown in human aortic endothelial cells upregulated nitric oxide on ischemia and suppressed monocyte adhesion that can be reversed by ectopic-expression of Arg1. Furthermore, chemical inhibition of Arg1 in wild-type mice had similar cardioprotection and reduced inflammation after MI as\n              <jats:italic>FoxO4<\/jats:italic>\n              inactivation and administration of nitric oxide synthase inhibitor to\n              <jats:italic>FoxO4<\/jats:italic>\n              KO mice reversed the beneficial effects of\n              <jats:italic>FoxO4<\/jats:italic>\n              deletion on post-MI cardiac function.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>FoxO4 activates Arg1 transcription in endothelial cells in response to MI, leading to downregulation of nitric oxide and upregulation of neutrophil infiltration to the infarct area.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.115.306919","type":"journal-article","created":{"date-parts":[[2015,10,6]],"date-time":"2015-10-06T02:58:57Z","timestamp":1444100337000},"page":"967-977","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":78,"title":["FoxO4 Promotes Early Inflammatory Response Upon Myocardial Infarction via Endothelial Arg1"],"prefix":"10.1161","volume":"117","author":[{"given":"Min","family":"Zhu","sequence":"first","affiliation":[{"name":"From the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA (S.M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean C.","family":"Goetsch","sequence":"additional","affiliation":[{"name":"From the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA (S.M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoning","family":"Wang","sequence":"additional","affiliation":[{"name":"From the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA (S.M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Luo","sequence":"additional","affiliation":[{"name":"From the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA (S.M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph A.","family":"Hill","sequence":"additional","affiliation":[{"name":"From the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA (S.M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay","family":"Schneider","sequence":"additional","affiliation":[{"name":"From the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA (S.M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Sidney M.","family":"Morris","sequence":"additional","affiliation":[{"name":"From the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); 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