{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T06:32:48Z","timestamp":1792477968782,"version":"4.5.0"},"reference-count":61,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Atherosclerosis progresses through endothelial dysfunction, vascular inflammation, endothelial-to-mesenchymal transition (EndMT), and plaque instability. While ANGPTL4 (angiopoietin-like 4) is known for its metabolic functions, its role in endothelial homeostasis remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We investigated the protective effects of ANGPTL4 on endothelial inflammation, vascular integrity, and EndMT using\n                      <jats:italic toggle=\"yes\">Apoe<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic toggle=\"yes\">\/<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      mice, human umbilical vein endothelial cells, human aortic endothelial cells, and induced pluripotent stem cell\u2013derived endothelial cells. EndMT features were also evaluated in human atherosclerotic plaques. In patients with coronary artery disease, we analyzed plasma ANGPTL4 levels in relation to coronary microvascular dysfunction, as assessed by coronary flow reserve and the index of microcirculatory resistance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>ANGPTL4 suppressed TNF-\u03b1 (tumor necrosis factor alpha)\u2013induced and IL-1\u03b2 (interleukin-1 beta)\u2013induced endothelial inflammation and preserved vascular barrier integrity in vitro and in vivo. It also inhibited TGF-\u03b2 (transforming growth factor-\u03b2)\u2013driven EndMT by restoring endothelial markers and suppressing mesenchymal marker expression. Mechanistically, ANGPTL4 attenuated TGF-\u03b2-Smad2 (suppressor of mothers against decapentaplegic 2) signaling and restored KLF2 (Kr\u00fcppel-like factor 2) expression, which was essential for its anti-inflammatory and anti-EndMT effects. KLF2 knockdown abolished ANGPTL4-mediated endothelial protection, confirming its pivotal role in maintaining endothelial identity. In human atherosclerotic plaques, EndMT marker expression strongly correlated with plaque complexity, suggesting that EndMT exacerbates atherosclerosis progression. Plasma ANGPTL4 levels were significantly reduced in patients with coronary artery disease with coronary microvascular dysfunction and were positively correlated with coronary flow reserve, supporting its potential as a biomarker and preventive modulator of endothelial dysfunction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>These findings identify ANGPTL4 as a critical modulator of endothelial inflammation and EndMT via suppression of TGF-\u03b2-Smad2 signaling and restoration of KLF2. By preserving vascular integrity and promoting endothelial homeostasis, ANGPTL4 may serve as a preventive modulator in EndMT-driven vascular pathology and coronary microvascular dysfunction.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.125.322700","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T09:00:17Z","timestamp":1755162017000},"page":"1742-1761","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["ANGPTL4 Prevents Atherosclerosis by Preserving KLF2 to Suppress EndMT and Mitigates Endothelial Dysfunction"],"prefix":"10.1161","volume":"45","author":[{"given":"Dong Im","family":"Cho","sequence":"first","affiliation":[{"name":"Cell Regeneration Research Center (D.I.C., B.G.K., I.H., H.H.C., J.H.J., J.Y., M.C., S.J.Y., Y.S.K., Y.A.), Chonnam National University Hospital, Gwangju, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joon Ho","family":"Ahn","sequence":"additional","affiliation":[{"name":"Department of Cardiology (J.H.A., Y.A.), Chonnam National University Hospital, Gwangju, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3883-8418","authenticated-orcid":true,"given":"Bo Gyeong","family":"Kang","sequence":"additional","affiliation":[{"name":"Cell Regeneration Research Center (D.I.C., B.G.K., I.H., H.H.C., J.H.J., J.Y., M.C., S.J.Y., Y.S.K., Y.A.), Chonnam National University Hospital, Gwangju, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0209-5763","authenticated-orcid":true,"given":"InJoo","family":"Hwang","sequence":"additional","affiliation":[{"name":"Cell Regeneration Research Center (D.I.C., B.G.K., I.H., H.H.C., J.H.J., J.Y., M.C., S.J.Y., Y.S.K., Y.A.), Chonnam National University Hospital, Gwangju, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyang Hee","family":"Cho","sequence":"additional","affiliation":[{"name":"Cell Regeneration Research Center (D.I.C., B.G.K., I.H., H.H.C., J.H.J., J.Y., M.C., S.J.Y., Y.S.K., Y.A.), Chonnam National University Hospital, Gwangju, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju Hee","family":"Jun","sequence":"additional","affiliation":[{"name":"Cell Regeneration Research Center (D.I.C., B.G.K., I.H., H.H.C., J.H.J., J.Y., M.C., S.J.Y., Y.S.K., Y.A.), Chonnam National University Hospital, Gwangju, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Yoo","sequence":"additional","affiliation":[{"name":"Cell Regeneration Research Center (D.I.C., B.G.K., I.H., H.H.C., J.H.J., J.Y., M.C., S.J.Y., Y.S.K., Y.A.), Chonnam National University Hospital, Gwangju, Republic of 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Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9483-5639","authenticated-orcid":true,"given":"Yong Sook","family":"Kim","sequence":"additional","affiliation":[{"name":"Cell Regeneration Research Center (D.I.C., B.G.K., I.H., H.H.C., J.H.J., J.Y., M.C., S.J.Y., Y.S.K., Y.A.), Chonnam National University Hospital, Gwangju, Republic of Korea."},{"name":"Biomedical Research Institute (Y.S.K.), Chonnam National University Hospital, Gwangju, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2022-9366","authenticated-orcid":true,"given":"Youngkeun","family":"Ahn","sequence":"additional","affiliation":[{"name":"Cell Regeneration Research Center (D.I.C., B.G.K., I.H., H.H.C., J.H.J., J.Y., M.C., S.J.Y., Y.S.K., Y.A.), Chonnam National University Hospital, Gwangju, Republic of Korea."},{"name":"Department of Cardiology (J.H.A., Y.A.), Chonnam National University Hospital, 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