Guang Yang1, Yanna Lei1, Aiko Inoue2, Limei Piao3, Lina Hu4, Haiying Jiang1, Takeshi Sasaki5, Hongxian Wu6, Wenhu Xu3, Chenglin Yu3, Guangxian Zhao1, Shinyu Ogasawara7, Kenji Okumura6, Masafumi Kuzuya2, Xian-Wu Cheng8. 1. Department of Cardiology and ICU, Yanbian University Hospital, Yanjin, Jilin PR., 13000, China. 2. Institute of Innovation for Future Society, Nagoya University, Nagoya, 4668550, Japan; Department of Community Health & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, 4668550, Japan. 3. Department of Cardiology and ICU, Yanbian University Hospital, Yanjin, Jilin PR., 13000, China; Institute of Innovation for Future Society, Nagoya University, Nagoya, 4668550, Japan. 4. Department of Public Health, Guilin Medical College, Guilin, Guangxi P. R., 541004, China. 5. Department of Anatomy and Neuroscience, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, 4313192, Japan. 6. Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China. 7. Institute of Innovation for Future Society, Nagoya University, Nagoya, 4668550, Japan. 8. Department of Cardiology and ICU, Yanbian University Hospital, Yanjin, Jilin PR., 13000, China; Institute of Innovation for Future Society, Nagoya University, Nagoya, 4668550, Japan; Department of Community Health & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, 4668550, Japan; Department of Internal Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea. Electronic address: xianwu@med.nagoya-u.ac.jp.
Abstract
BACKGROUND AND AIMS: Exposure to psychosocial stress is a risk factor for cardiovascular disorders. Because the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonist prevents cardiovascular injury, we investigated the beneficial effects and mechanism of the GLP-1 analogue exenatide on stress-related vascular senescence and atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat (HF) diet. METHODS: ApoE-/- mice fed the HF diet were assigned to non-stressed and immobilized-stress groups for 12 weeks. Mice fed the HF diet were divided into 2 groups and administered vehicle or exenatide for 12 weeks under stress conditions. RESULTS: Chronic stress enhanced vascular endothelial senescence and atherosclerotic plaque growth. The stress increased the levels of plasma depeptidyl peptidase-4 activity and decreased the levels of plasma GLP-1 and both plasma and adipose adiponectin (APN). As compared with the mice subjected to stress alone, the exenatide-treated mice had decreased plaque microvessel density, macrophage accumulation, broken elastin, and enhanced plaque collagen volume, and lowered levels of peroxisome proliferator-activated receptor-α, gp91phox osteopontin, C-X-C chemokine receptor-4, toll-like receptor-2 (TLR2), TLR4, and cathepsins K, L, and S mRNAs and/or proteins. Exenatide reduced aortic matrix metalloproteinase-9 (MMP-9) and MMP-2 gene expression and activities. Exenatide also stimulated APN expression of preadipocytes and inhibited ox-low density lipoprotein-induced foam cell formation of monocytes in stressed mice. CONCLUSIONS: These results indicate that the exenatide-mediated beneficial vascular actions are likely attributable, at least in part, to the enhancement of APN production and the attenuation of plaque oxidative stress, inflammation, and proteolysis in ApoE-/- mice under chronic stress.
BACKGROUND AND AIMS: Exposure to psychosocial stress is a risk factor for cardiovascular disorders. Because the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonist prevents cardiovascular injury, we investigated the beneficial effects and mechanism of the GLP-1 analogue exenatide on stress-related vascular senescence and atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat (HF) diet. METHODS:ApoE-/- mice fed the HF diet were assigned to non-stressed and immobilized-stress groups for 12 weeks. Mice fed the HF diet were divided into 2 groups and administered vehicle or exenatide for 12 weeks under stress conditions. RESULTS: Chronic stress enhanced vascular endothelial senescence and atherosclerotic plaque growth. The stress increased the levels of plasma depeptidyl peptidase-4 activity and decreased the levels of plasma GLP-1 and both plasma and adipose adiponectin (APN). As compared with the mice subjected to stress alone, the exenatide-treated mice had decreased plaque microvessel density, macrophage accumulation, broken elastin, and enhanced plaque collagen volume, and lowered levels of peroxisome proliferator-activated receptor-α, gp91phox osteopontin, C-X-C chemokine receptor-4, toll-like receptor-2 (TLR2), TLR4, and cathepsins K, L, and S mRNAs and/or proteins. Exenatide reduced aortic matrix metalloproteinase-9 (MMP-9) and MMP-2 gene expression and activities. Exenatide also stimulated APN expression of preadipocytes and inhibited ox-low density lipoprotein-induced foam cell formation of monocytes in stressed mice. CONCLUSIONS: These results indicate that the exenatide-mediated beneficial vascular actions are likely attributable, at least in part, to the enhancement of APN production and the attenuation of plaque oxidative stress, inflammation, and proteolysis in ApoE-/- mice under chronic stress.
Authors: Lars Brodowski; Tristan Zindler; Sandra von Hardenberg; Bianca Schröder-Heurich; Constantin S von Kaisenberg; Helge Frieling; Carl A Hubel; Thilo Dörk; Frauke von Versen-Höynck Journal: Front Cell Dev Biol Date: 2019-03-19