{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T03:54:21Z","timestamp":1791345261560,"version":"4.3.1"},"reference-count":36,"publisher":"Rockefeller University Press","issue":"8","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,7,28]]},"abstract":"<jats:p>N-3 polyunsaturated fatty acids (PUFAs) have potential cardiovascular benefit, although the mechanisms underlying this effect remain poorly understood. Fat-1 transgenic mice expressing Caenorhabditis elegans n-3 fatty acid desaturase, which is capable of producing n-3 PUFAs from n-6 PUFAs, exhibited resistance to pressure overload\u2013induced inflammation and fibrosis, as well as reduced cardiac function. Lipidomic analysis revealed selective enrichment of eicosapentaenoic acid (EPA) in fat-1 transgenic bone marrow (BM) cells and EPA-metabolite 18-hydroxyeicosapentaenoic acid (18-HEPE) in fat-1 transgenic macrophages. BM transplantation experiments revealed that fat-1 transgenic BM cells, but not fat-1 transgenic cardiac cells, contributed to the antiremodeling effect and that the 18-HEPE\u2013rich milieu in the fat-1 transgenic heart was generated by BM-derived cells, most likely macrophages. 18-HEPE inhibited macrophage-mediated proinflammatory activation of cardiac fibroblasts in culture, and in vivo administration of 18-HEPE reproduced the fat-1 mice phenotype, including resistance to pressure overload\u2013induced maladaptive cardiac remodeling.<\/jats:p>","DOI":"10.1084\/jem.20132011","type":"journal-article","created":{"date-parts":[[2014,7,22]],"date-time":"2014-07-22T01:51:47Z","timestamp":1405993907000},"page":"1673-1687","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":159,"title":["18-HEPE, an n-3 fatty acid metabolite released by macrophages, prevents pressure overload\u2013induced maladaptive cardiac remodeling"],"prefix":"10.1084","volume":"211","author":[{"given":"Jin","family":"Endo","sequence":"first","affiliation":[{"name":"Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan 1"},{"name":"Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan 2"},{"name":"Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoaki","family":"Sano","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke","family":"Isobe","sequence":"additional","affiliation":[{"name":"Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan 1"},{"name":"Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiichi","family":"Fukuda","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing X.","family":"Kang","sequence":"additional","affiliation":[{"name":"Laboratory for Lipid Medicine and Technology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Arai","sequence":"additional","affiliation":[{"name":"Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Arita","sequence":"additional","affiliation":[{"name":"Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan 1"},{"name":"Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan 2"},{"name":"PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan 5"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2014,7,21]]},"reference":[{"key":"2023072602322943200_bib1","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1093\/jb\/mvs092","article-title":"Mediator lipidomics in acute inflammation and resolution","volume":"152","author":"Arita","year":"2012","journal-title":"J. Biochem."},{"key":"2023072602322943200_bib2","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1139\/o59-099","article-title":"A rapid method of total lipid extraction and purification","volume":"37","author":"Bligh","year":"1959","journal-title":"Can. J. Biochem. Physiol."},{"key":"2023072602322943200_bib3","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1161\/CIRCULATIONAHA.110.971853","article-title":"Omega-3 fatty acids prevent pressure overload-induced cardiac fibrosis through activation of cyclic GMP\/protein kinase G signaling in cardiac fibroblasts","volume":"123","author":"Chen","year":"2011","journal-title":"Circulation."},{"key":"2023072602322943200_bib4","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1016\/j.cardiores.2007.07.002","article-title":"Dietary supplementation with \u03c9-3 PUFA increases adiponectin and attenuates ventricular remodeling and dysfunction with pressure overload","volume":"76","author":"Duda","year":"2007","journal-title":"Cardiovasc. Res."},{"key":"2023072602322943200_bib5","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.1161\/CIRCULATIONAHA.106.650903","article-title":"Bone marrow derived cells are involved in the pathogenesis of cardiac hypertrophy in response to pressure overload","volume":"116","author":"Endo","year":"2007","journal-title":"Circulation."},{"key":"2023072602322943200_bib6","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.immuni.2013.11.019","article-title":"Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation","volume":"40","author":"Epelman","year":"2014","journal-title":"Immunity."},{"key":"2023072602322943200_bib7","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1146\/annurev.nutr.25.050304.092610","article-title":"Fatty acids as modulators of the immune response","volume":"26","author":"Fritsche","year":"2006","journal-title":"Annu. Rev. Nutr."},{"key":"2023072602322943200_bib8","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1016\/j.mehy.2012.07.035","article-title":"Intra-articular lentivirus-mediated insertion of the fat-1 gene ameliorates osteoarthritis","volume":"79","author":"Huang","year":"2012","journal-title":"Med. Hypotheses."},{"key":"2023072602322943200_bib9","doi-asserted-by":"publisher","first-page":"11276","DOI":"10.1073\/pnas.0601280103","article-title":"Transgenic mice rich in endogenous omega-3 fatty acids are protected from colitis","volume":"103","author":"Hudert","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072602322943200_bib10","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1093\/jb\/mvs151","article-title":"Stereochemical assignment and anti-inflammatory properties of the omega-3 lipid mediator resolvin E3","volume":"153","author":"Isobe","year":"2013","journal-title":"J. Biochem."},{"key":"2023072602322943200_bib11","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1291\/hypres.29.711","article-title":"Pressure overload-induced transient oxidative stress mediates perivascular inflammation and cardiac fibrosis through angiotensin II","volume":"29","author":"Kai","year":"2006","journal-title":"Hypertens. Res."},{"key":"2023072602322943200_bib12","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1038\/427504a","article-title":"Transgenic mice: fat-1 mice convert n-6 to n-3 fatty acids","volume":"427","author":"Kang","year":"2004","journal-title":"Nature."},{"key":"2023072602322943200_bib13","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.1084\/jem.20082596","article-title":"Cardiac 12\/15 lipoxygenase-induced inflammation is involved in heart failure","volume":"206","author":"Kayama","year":"2009","journal-title":"J. Exp. Med."},{"key":"2023072602322943200_bib14","doi-asserted-by":"publisher","first-page":"2243","DOI":"10.1161\/01.CIR.102.18.2243","article-title":"Role of monocyte chemoattractant protein-1 in cardiovascular remodeling induced by chronic blockade of nitric oxide synthesis","volume":"102","author":"Koyanagi","year":"2000","journal-title":"Circulation."},{"key":"2023072602322943200_bib15","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1161\/01.HYP.0000118584.33350.7d","article-title":"Hypertensive myocardial fibrosis and diastolic dysfunction: another model of inflammation?","volume":"43","author":"Kuwahara","year":"2004","journal-title":"Hypertension."},{"key":"2023072602322943200_bib16","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1084\/jem.20111009","article-title":"Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis","volume":"209","author":"Leuschner","year":"2012","journal-title":"J. Exp. Med."},{"key":"2023072602322943200_bib17","doi-asserted-by":"publisher","first-page":"e35144","DOI":"10.1371\/journal.pone.0035144","article-title":"Macrophage-stimulated cardiac fibroblast production of IL-6 is essential for TGF \u03b2\/Smad activation and cardiac fibrosis induced by angiotensin II","volume":"7","author":"Ma","year":"2012","journal-title":"PLoS ONE."},{"key":"2023072602322943200_bib18","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1161\/HYPERTENSIONAHA.109.148635","article-title":"Interleukin 6 mediates myocardial fibrosis, concentric hypertrophy, and diastolic dysfunction in rats","volume":"56","author":"Mel\u00e9ndez","year":"2010","journal-title":"Hypertension."},{"key":"2023072602322943200_bib19","doi-asserted-by":"publisher","first-page":"2047","DOI":"10.1016\/j.jacc.2011.06.063","article-title":"Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events","volume":"58","author":"Mozaffarian","year":"2011","journal-title":"J. Am. Coll. Cardiol."},{"key":"2023072602322943200_bib20","doi-asserted-by":"publisher","first-page":"3037","DOI":"10.1084\/jem.20070885","article-title":"The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions","volume":"204","author":"Nahrendorf","year":"2007","journal-title":"J. Exp. Med."},{"key":"2023072602322943200_bib21","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.1016\/S0008-6363(96)00158-7","article-title":"Inflammatory cells and myocardial fibrosis: spatial and temporal distribution in renovascular hypertensive rats","volume":"32","author":"Nicoletti","year":"1996","journal-title":"Cardiovasc. Res."},{"key":"2023072602322943200_bib22","doi-asserted-by":"publisher","first-page":"870","DOI":"10.1016\/j.jacc.2010.11.017","article-title":"Effects of n-3 polyunsaturated fatty acids on left ventricular function and functional capacity in patients with dilated cardiomyopathy","volume":"57","author":"Nodari","year":"2011","journal-title":"J. Am. Coll. Cardiol."},{"key":"2023072602322943200_bib23","doi-asserted-by":"publisher","first-page":"3602","DOI":"10.1021\/ol901350g","article-title":"Total synthesis and bioactivity of resolvin E2","volume":"11","author":"Ogawa","year":"2009","journal-title":"Org. Lett."},{"key":"2023072602322943200_bib24","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1016\/j.cell.2010.07.041","article-title":"GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects","volume":"142","author":"Oh","year":"2010","journal-title":"Cell."},{"key":"2023072602322943200_bib25","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1016\/S0140-6736(06)68074-4","article-title":"Controversies in ventricular remodelling","volume":"367","author":"Opie","year":"2006","journal-title":"Lancet."},{"key":"2023072602322943200_bib26","doi-asserted-by":"publisher","first-page":"29717","DOI":"10.1074\/jbc.M003128200","article-title":"Interleukin-6 family of cytokines mediate angiotensin II-induced cardiac hypertrophy in rodent cardiomyocytes","volume":"275","author":"Sano","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2023072602322943200_bib27","doi-asserted-by":"publisher","first-page":"1223","DOI":"10.1016\/S0140-6736(08)61239-8","article-title":"Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial","volume":"372","author":"Tavazzi","year":"2008","journal-title":"Lancet."},{"key":"2023072602322943200_bib28","doi-asserted-by":"publisher","first-page":"2487","DOI":"10.1161\/ATVBAHA.110.210054","article-title":"Endogenously decreasing tissue n-6\/n-3 fatty acid ratio reduces atherosclerotic lesions in apolipoprotein E-deficient mice by inhibiting systemic and vascular inflammation","volume":"30","author":"Wan","year":"2010","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2023072602322943200_bib29","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1038\/nrcardio.2012.158","article-title":"Myofibroblast-mediated mechanisms of pathological remodelling of the heart","volume":"10","author":"Weber","year":"2013","journal-title":"Nat. Rev. Cardiol."},{"key":"2023072602322943200_bib30","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1016\/j.bbadis.2008.08.011","article-title":"Reduction of inflammation and chronic tissue damage by omega-3 fatty acids in fat-1 transgenic mice with pancreatitis","volume":"1782","author":"Weylandt","year":"2008","journal-title":"Biochim. Biophys. Acta."},{"key":"2023072602322943200_bib31","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1093\/carcin\/bgr049","article-title":"Suppressed liver tumorigenesis in fat-1 mice with elevated omega-3 fatty acids is associated with increased omega-3 derived lipid mediators and reduced TNF-\u03b1","volume":"32","author":"Weylandt","year":"2011","journal-title":"Carcinogenesis."},{"key":"2023072602322943200_bib32","doi-asserted-by":"publisher","first-page":"3066","DOI":"10.2337\/db10-0054","article-title":"Transgenic restoration of long-chain n-3 fatty acids in insulin target tissues improves resolution capacity and alleviates obesity-linked inflammation and insulin resistance in high-fat-fed mice","volume":"59","author":"White","year":"2010","journal-title":"Diabetes."},{"key":"2023072602322943200_bib33","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.1038\/nm.2807","article-title":"Mechanisms of fibrosis: therapeutic translation for fibrotic disease","volume":"18","author":"Wynn","year":"2012","journal-title":"Nat. Med."},{"key":"2023072602322943200_bib34","doi-asserted-by":"publisher","first-page":"12499","DOI":"10.1073\/pnas.0605394103","article-title":"Melanoma growth is reduced in fat-1 transgenic mice: impact of omega-6\/omega-3 essential fatty acids","volume":"103","author":"Xia","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072602322943200_bib35","doi-asserted-by":"publisher","first-page":"1090","DOI":"10.1016\/S0140-6736(07)60527-3","article-title":"Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis","volume":"369","author":"Yokoyama","year":"2007","journal-title":"Lancet."},{"key":"2023072602322943200_bib36","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1146\/annurev-nutr-071811-150726","article-title":"Resolvins: anti-inflammatory and proresolving mediators derived from omega-3 polyunsaturated fatty acids","volume":"32","author":"Zhang","year":"2012","journal-title":"Annu. Rev. Nutr."}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/211\/8\/1673\/1751768\/jem_20132011.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/211\/8\/1673\/1751768\/jem_20132011.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T22:33:04Z","timestamp":1690324384000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/211\/8\/1673\/41723\/18-HEPE-an-n-3-fatty-acid-metabolite-released-by"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,7,21]]},"references-count":36,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2014,7,28]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20132011","relation":{},"ISSN":["1540-9538","0022-1007"],"issn-type":[{"value":"1540-9538","type":"electronic"},{"value":"0022-1007","type":"print"}],"subject":[],"published":{"date-parts":[[2014,7,21]]}}}