Mizuho Hiramatsu-Ito1, Rei Shibata2, Koji Ohashi3, Yusuke Uemura1, Noriyoshi Kanemura1, Takahiro Kambara1, Takashi Enomoto1, Daisuke Yuasa1, Kazuhiro Matsuo1, Masanori Ito1, Satoko Hayakawa1, Hayato Ogawa1, Naoya Otaka1, Shinji Kihara4, Toyoaki Murohara1, Noriyuki Ouchi5. 1. Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan. 2. Department of Advanced Cardiovascular Therapeutics, Nagoya University Graduate School of Medicine, Nagoya, Japan nouchi@med.nagoya-u.ac.jp rshibata@med.nagaya-u.ac.jp. 3. Molecular Cardiovascular Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya 466-8550, Japan. 4. Department of Biomedical Informatics, Osaka University Graduate School of Medicine, Osaka, Japan. 5. Molecular Cardiovascular Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya 466-8550, Japan nouchi@med.nagoya-u.ac.jp rshibata@med.nagaya-u.ac.jp.
Abstract
AIMS: Obesity is associated with the development of atherosclerosis. We previously demonstrated that omentin is a circulating adipokine that is downregulated in association with atherosclerotic diseases. Here, we examined the impact of omentin on the development of atherosclerosis with gain-of-function genetic manipulations and dissected its potential mechanism. METHODS AND RESULTS: Apolipoprotein E-deficient (apoE-KO) mice were crossed with transgenic mice expressing the human omentin gene (OMT-Tg) mice in fat tissue to generate apoE-KO/OMT-Tg mice. ApoE-KO/OMT-Tg mice exhibited a significant reduction of the atherosclerotic areas in aortic sinus, compared with apoE-KO mice despite similar lipid levels. ApoE-KO/OMT-Tg mice also displayed significant decreases in macrophage accumulation and mRNA expression of proinflammatory mediators including tumour necrosis factor-α, interleukin-6, and monocyte chemotactic protein-1 in aorta when compared with apoE-KO mice. Treatment of human monocyte-derived macrophages with a physiological concentration of human omentin protein led to reduction of lipid droplets and cholesteryl ester content. Treatment with human omentin protein also reduced lipopolysaccharide-induced expression of proinflammatory genes in human macrophages. Treatment of human macrophages with omentin promoted the phosphorylation of Akt. Inhibition of Akt signalling abolished the anti-inflammatory actions of omentin in macrophages. CONCLUSION: These data document for the first time that omentin reduces the development of atherosclerosis by reducing inflammatory response of macrophages through the Akt-dependent mechanisms. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Obesity is associated with the development of atherosclerosis. We previously demonstrated that omentin is a circulating adipokine that is downregulated in association with atherosclerotic diseases. Here, we examined the impact of omentin on the development of atherosclerosis with gain-of-function genetic manipulations and dissected its potential mechanism. METHODS AND RESULTS: Apolipoprotein E-deficient (apoE-KO) mice were crossed with transgenic mice expressing the humanomentin gene (OMT-Tg) mice in fat tissue to generate apoE-KO/OMT-Tg mice. ApoE-KO/OMT-Tg mice exhibited a significant reduction of the atherosclerotic areas in aortic sinus, compared with apoE-KO mice despite similar lipid levels. ApoE-KO/OMT-Tg mice also displayed significant decreases in macrophage accumulation and mRNA expression of proinflammatory mediators including tumour necrosis factor-α, interleukin-6, and monocyte chemotactic protein-1 in aorta when compared with apoE-KO mice. Treatment of human monocyte-derived macrophages with a physiological concentration of humanomentin protein led to reduction of lipid droplets and cholesteryl ester content. Treatment with humanomentin protein also reduced lipopolysaccharide-induced expression of proinflammatory genes in human macrophages. Treatment of human macrophages with omentin promoted the phosphorylation of Akt. Inhibition of Akt signalling abolished the anti-inflammatory actions of omentin in macrophages. CONCLUSION: These data document for the first time that omentin reduces the development of atherosclerosis by reducing inflammatory response of macrophages through the Akt-dependent mechanisms. Published on behalf of the European Society of Cardiology. All rights reserved.