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JST Press Release

July 24, 2014
Japan Science and Technology Agency (JST)
5-3, Yonbancho, Chiyoda-ku, Tokyo 102-8666
URL http://www.jst.go.jp/EN/index.html

Genetic and lipidomic approach uncovers cardioprotective mechanism by omega-3 fatty acid

Omega-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), is widely held to be cardioprotective with epidemiological evidence of people who consumed omega-3 PUFA-rich diet having a low incidence of cardiovascular death. Increased cardiac afterload is responsible for the pathogenesis and progression of heart failure accompanied by maladaptive cardiac remodeling, namely cardiomyocyte hypertrophy, inflammatory cell infiltration and fibrosis. Cardioprotective effect of omega-3 PUFAs in the setting of chronic heart failure can be explained by the anti-inflammatory and/or anti-remodeling activities, although the direct evidence and mechanisms underlying such effects have been unclear.

Now, Drs. Makoto Arita, Jin Endo and colleagues from RIKEN Center for Integrative Medical Sciences (IMS), University of Tokyo Graduate School of Pharmaceutical Sciences, and Keio University School of Medicine show that fat-1 transgenic mice expressing C. elegans omega-3 fatty acid desaturase, which is capable of producing omega-3 PUFAs endogenously, exhibited resistance to pressure overload-induced cardiac remodeling as well as reduced cardiac function. Bone marrow (BM) transplantation experiments revealed that fat-1 transgenic BM cells, but not fat-1 transgenic cardiac cells, contributed to the anti-remodeling effect. Lipidomic analysis revealed selective enrichment of EPA and EPA-metabolite 18-HEPE in fat-1 transgenic macrophages, and that the 18-HEPE-rich milieu in the fat-1 transgenic heart was generated by BM-derived macrophages. 18-HEPE inhibited 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-induced maladaptive cardiac remodeling. The use of 18-HEPE may lead to a novel therapeutic application for heart failure based on anti-inflammatory and anti-fibrotic lipid mediators.

Researcher Information

Research Area: “Elucidation and control of the mechanisms underlying chronic inflammation”
Research Theme: “Establishing the molecular bases of resolution of inflammation as potential therapeutic targets for chronic diseases”

Journal Information

Jin Endo, Motoaki Sano, Yosuke Isobe, Keiichi Fukuda, Jing X Kang, Hiroyuki Arai, and Makoto Arita.
“18-HEPE, an n-3 fatty acid metabolite released by macrophages, prevents pressure overload-induced maladaptive cardiac remodeling”
The Journal of Experimental Medicine
Published online: July 21, 2014
doi: 10.1084/jem.20132011


[About Research]
Makoto Arita, Ph.D.
Team Leader, Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences (IMS)

[About Program]
Koji Matsuo, Takafumi Kawaguchi, and Toshiyuki Shingo
Life Innovation Group, Department of Innovation Research, Japan Science and Technology Agency


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