title: EPA Prevents the Development of Abdominal Aortic Aneurysms through Gpr-120/Ffar-4.
abstract: Abdominal aortic aneurysms (AAAs), which commonly occur among elderly individuals, are accompanied by a risk of rupture with a high mortality rate. Although eicosapentaenoic acid (EPA) has been reported to prevent AAA formation, the mechanism by which EPA works on vascular smooth muscle cells is unknown. This study aimed to investigate the mechanism by which orally-administered EPA prevents the formation of severe AAAs that develop in Osteoprotegerin (Opg) knockout (KO) mice. In the CaCl2-induced AAA model, EPA attenuated the enhanced progression of AAAs in Opg-KO mice, including the increase in aortic diameter with destruction of elastic fibers in the media. Immunohistochemical analyses showed that EPA reduced the phosphorylation of transforming growth factor beta-activated kinase-1/Map3k7 (Tak-1) and c-Jun NH2-terminal kinase (JNK), as well as the expression of Matrix metalloproteinase-9 (Mmp-9) in the media of the aorta. In smooth muscle cell cultures, rh-TRAIL-induced activation of the Tak-1-JNK pathway and increase in Mmp-9 expression were inhibited by EPA. Moreover, GW9508, a specific ligand for G-protein coupled receptor (Gpr)-120/Free fatty acid receptor (Ffar)-4, mimicked the effects of EPA. The effects of EPA were abrogated by knockdown of the Gpr-120/Ffar-4 receptor gene. Our data demonstrate that the Trail-Tak-1-JNK-Mmp-9 pathway is responsible for the enhancement of AAAs in Opg-KO mice, and that EPA inhibits the Tak-1-JNK pathway by activating Gpr-120/Ffar-4, which results in the attenuation of AAA development.
authors.affiliation: Department of Cardiovascular Physiology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Kamata
authors.affiliation: Department of Cardiovascular Physiology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Batmunkh
authors.initials: B
authors.lastname: Bumdelger
authors.affiliation: Department of Cardiovascular Physiology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kokubo
authors.affiliation: Department of Cardiovascular Physiology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujii
authors.affiliation: Department of Surgery and Clinical Science, Graduate School of Medicine, Yamaguchi University, Ube, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Yoshimura
authors.affiliation: Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Ishida
authors.affiliation: Department of Cardiovascular Physiology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Ishida
authors.affiliation: Department of Cardiovascular Physiology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Yoshizumi
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D002122:Calcium Chloride / Q000633:toxicity; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D015118:Eicosapentaenoic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008744:Methylamines / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053244:Osteoprotegerin / Q000172:deficiency / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D002122:Calcium Chloride; D015118:Eicosapentaenoic Acid; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D020780:Matrix Metalloproteinase 9; D008744:Methylamines; D053244:Osteoprotegerin; D011422:Propionates; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D000099151:MAP Kinase Kinase Kinase 7; C498007:FFAR4 protein, mouse; C515630:GW9508