EPA Prevents the Development of Abdominal Aortic Aneurysms through Gpr-120/Ffar-4.

Ryo Kamata,Masao Yoshizumi,Mari Ishida,Batmunkh Bumdelger,Takafumi Ishida,Koichi Yoshimura,Masayuki Fujii,Hiroki Kokubo,Utako Yokoyama

doi:10.1371/journal.pone.0165132

Ryo Kamata, Masao Yoshizumi + Show 7 more

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https://doi.org/10.1371/journal.pone.0165132

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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.

Highlights

An abdominal aortic aneurysm (AAA) is a condition in which the abdominal aorta is expanded, leading to rupture with a high mortality rate
Our findings suggest that eicosapentaenoic acid (EPA) can prevent the enlargement of AAAs by activating Gprotein coupled receptor (Gpr)-120/Free fatty acid receptor (Ffar)-4-mediated signaling in aortic smooth muscle cells (SMCs)
In order to examine whether EPA attenuates the development of AAA in Opg-KO mice, we first measured the size of the aorta in wild-type and Opg-KO mice, which were fed a diet with (+) or without (-) EPA starting two weeks before AAA induction[7], [15]

Summary

Introduction

An abdominal aortic aneurysm (AAA) is a condition in which the abdominal aorta is expanded, leading to rupture with a high mortality rate. Destruction of medial elastic fibers and infiltration of macrophages into AAA lesions are considered as the main causes of AAA formation[1]. Degradation of aortic medial elastic fibers may be induced by imbalances. EPA Prevents AAA through Gpr-120/Ffar between the proteolytic activities of matrix metalloproteinases, such as MMP-2 and MMP-9, and their inhibitors, the tissue inhibitors of metalloproteinases (Timp-1). The expression of both is reported to be elevated during aneurysm development[2,3,4,5,6]. Pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL), are known to activate the JNK pathway[9]

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