{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:46:32Z","timestamp":1791474392341,"version":"4.3.4"},"reference-count":27,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2015,6,19]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Apolipoprotein E (apoE) exerts anti-inflammatory properties that protect against atherosclerosis and other inflammatory diseases. However, mechanisms by which apoE suppresses the cellular activation of leukocytes commonly associated with atherosclerosis remain incompletely understood.<\/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 apoE suppresses inflammation and atherosclerosis by regulating cellular microRNA levels in these leukocytes.<\/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              An assessment of apoE expression among such leukocyte subsets in wild-type mice revealed that only macrophages and monocytes express apoE abundantly. An absence of apoE expression in macrophages and monocytes resulted in enhanced nuclear factor-\u03baB signaling and an exaggerated inflammatory response on stimulation with lipopolysaccharide. This correlated with reduced levels of microRNA-146a, a critical negative regulator of nuclear factor-\u03baB signaling. Ectopic apoE expression in\n              <jats:italic>Apoe<\/jats:italic>\n              <jats:sup>\u2013\/\u2013<\/jats:sup>\n              macrophages and monocytes raised miR-146a levels, whereas its silencing in wild-type cells had an opposite effect. Mechanistically, apoE increased the expression of transcription factor purine-rich PU-box\u2013binding protein 1, which raised levels of pri-miR-146 transcripts, demonstrating that apoE exerts transcriptional control over miR-146a. In vivo, even a small amount of apoE expression in macrophages and monocytes of hypomorphic apoE mice led to increased miR-146a levels, and inhibited macrophage proinflammatory responses, Ly-6C\n              <jats:sup>high<\/jats:sup>\n              monocytosis, and atherosclerosis in the settings of hyperlipidemia. Accordingly, cellular enrichment of miR-146a through the systemic delivery of miR-146a mimetics in\n              <jats:italic>Apoe<\/jats:italic>\n              <jats:sup>\u2013\/\u2013<\/jats:sup>\n              <jats:italic>Ldlr<\/jats:italic>\n              <jats:sup>\u2013\/\u2013<\/jats:sup>\n              and\n              <jats:italic>Ldlr<\/jats:italic>\n              <jats:sup>\u2013\/\u2013<\/jats:sup>\n              mice attenuated monocyte\/macrophage activation and atherosclerosis in the absence of plasma lipid reduction.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Our data demonstrate that cellular apoE expression suppresses nuclear factor-\u03baB\u2013mediated inflammation and atherosclerosis by enhancing miR-146a levels in monocytes and macrophages.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.117.305844","type":"journal-article","created":{"date-parts":[[2015,4,23]],"date-time":"2015-04-23T00:47:10Z","timestamp":1429750030000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":192,"title":["Apolipoprotein E Enhances MicroRNA-146a in Monocytes and Macrophages to Suppress Nuclear Factor-\u03baB\u2013Driven Inflammation and Atherosclerosis"],"prefix":"10.1161","volume":"117","author":[{"given":"Kang","family":"Li","sequence":"first","affiliation":[{"name":"From the Division of Vascular and Endovascular Surgery, Department of Surgery, University of California San Francisco and Veterans Affairs Medical Center."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Ching","sequence":"additional","affiliation":[{"name":"From the Division of Vascular and Endovascular Surgery, Department of Surgery, University of California San Francisco and Veterans Affairs Medical Center."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fu Sang","family":"Luk","sequence":"additional","affiliation":[{"name":"From the Division of Vascular and Endovascular Surgery, Department of Surgery, University of California San Francisco and Veterans Affairs Medical Center."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert L.","family":"Raffai","sequence":"additional","affiliation":[{"name":"From the Division of Vascular and Endovascular Surgery, Department of Surgery, University of California San Francisco and Veterans Affairs Medical Center."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/00041433-200006000-00004"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000187467.67684.43"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)32147-7"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1002847"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.111.222745"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.04.005"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.104.498865"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0709011104"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0403249101"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0605298103"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.113.302089"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R800056-JLR200"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2957"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI61716"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20101823"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-02-335141"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI29950"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111222200"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.111.238964"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000154570.50696.2c"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1097\/MOL.0b013e328356f967"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.9.4647"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI57559"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2012.02.009"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000152613.83243.12"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2012.09.018"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3838"}],"container-title":["Circulation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCRESAHA.117.305844","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T03:40:31Z","timestamp":1715571631000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCRESAHA.117.305844"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,6,19]]},"references-count":27,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2015,6,19]]}},"alternative-id":["10.1161\/CIRCRESAHA.117.305844"],"URL":"https:\/\/doi.org\/10.1161\/circresaha.117.305844","relation":{},"ISSN":["0009-7330","1524-4571"],"issn-type":[{"value":"0009-7330","type":"print"},{"value":"1524-4571","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,6,19]]},"assertion":[{"value":"2015-12-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-04-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-04-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}