Yanna Lei1, Guang Yang2, Lina Hu3, Limei Piao2, Aiko Inoue1, Haiying Jiang4, Takeshi Sasaki5, Guangxian Zhao1, Maimaiti Yisireyili6, Chenglin Yu1, Wenhu Xu1, Kyosuke Takeshita6, Kenji Okumura6, Masafumi Kuzuya7, Xian Wu Cheng8. 1. Department of ICU and Cardiology, Yanbian University Hospital, Yanji 133000, Jilin, PR China. 2. Department of ICU and Cardiology, Yanbian University Hospital, Yanji 133000, Jilin, PR China; Department of Community Health & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. 3. Department of Public Health, Guilin Medical College, Guilin 541004, Guangxi, PR China. 4. Department of Physiology and Pathophysiology, Yanbian University College of Medicine, Yanji 133000, Jilin, PR China. 5. Department of Anatomy and Neuroscience, Hamamatsu University School of Medicine, Hamamatsu 4313192, Shizuokaken, Japan. 6. Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Aichiken, Japan; Division of Cardiology, Department of Internal Medicine, Kyung Hee University, Seoul 02447, South Korea. 7. Department of Community Health & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Institute of Innovation for Future Society, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Aichiken, Japan. 8. Department of ICU and Cardiology, Yanbian University Hospital, Yanji 133000, Jilin, PR China; Department of Community Health & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Division of Cardiology, Department of Internal Medicine, Kyung Hee University, Seoul 02447, South Korea; Institute of Innovation for Future Society, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Aichiken, Japan. Electronic address: chengxw0908@163.com.
Abstract
OBJECTIVES: Exposure to psychosocial stress is a risk factor for cardiovascular disease. Given that dipeptidyl peptidase-4 (DPP4) regulates several intracellular signaling pathways associated with glucagon-like peptide-1 (GLP-1) metabolism, we investigated the role of DPP4 in stress-related vascular senescence and atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice. METHODS AND RESULTS: ApoE-/- mice fed a high-fat (HF) diet were randomly assigned to one of non-stress and immobilized stress groups for 12weeks. Chronic stress accelerated vascular senescence and atherosclerotic plaque growth at the aortic roots. Stressed mice had increased levels of plasma DPP4 and decreased levels of plasma GLP-1 and adiponectin (APN) and adipose APN expression. Stress increased plaque macrophage infiltration, neovessel density, and elastin fragmentation, lessened the plaque collagen content, and increased the levels of toll-like receptor-2 (TLR2), TLR4, C-X-C chemokine receptor-4, cathepsins S and K, osteopontin, peroxisome proliferator-activated receptor-α, p16INK4A, p21, and gp91phox mRNAs and/or proteins. Stressed aortas had also increased matrix metalloproteinase-2 (MMP-2) and MMP-9 activities. DPP4 inhibition with anagliptin reversed stress-related atherosclerotic lesion formation, and this benefit was abrogated by APN blocking. In vitro, the GLP-1 receptor agonist exenatide stimulated APN expression in 3T3-L1 cells. CONCLUSIONS: These results indicate that the DPP4 inhibition-mediated benefits are likely attributable, at least in part, to attenuation of plaque inflammation, oxidative stress and proteolysis associated with GLP-1-mediated APN production in ApoE-/- mice under stress. Thus, DPP4 will be a novel therapeutic target for the treatment of stress-related cardiovascular disease.
OBJECTIVES: Exposure to psychosocial stress is a risk factor for cardiovascular disease. Given that dipeptidyl peptidase-4 (DPP4) regulates several intracellular signaling pathways associated with glucagon-like peptide-1 (GLP-1) metabolism, we investigated the role of DPP4 in stress-related vascular senescence and atherosclerosis in apolipoprotein E-deficient (ApoE-/-)mice. METHODS AND RESULTS:ApoE-/- mice fed a high-fat (HF) diet were randomly assigned to one of non-stress and immobilized stress groups for 12weeks. Chronic stress accelerated vascular senescence and atherosclerotic plaque growth at the aortic roots. Stressed mice had increased levels of plasma DPP4 and decreased levels of plasma GLP-1 and adiponectin (APN) and adipose APN expression. Stress increased plaque macrophage infiltration, neovessel density, and elastin fragmentation, lessened the plaque collagen content, and increased the levels of toll-like receptor-2 (TLR2), TLR4, C-X-C chemokine receptor-4, cathepsins S and K, osteopontin, peroxisome proliferator-activated receptor-α, p16INK4A, p21, and gp91phox mRNAs and/or proteins. Stressed aortas had also increased matrix metalloproteinase-2 (MMP-2) and MMP-9 activities. DPP4 inhibition with anagliptin reversed stress-related atherosclerotic lesion formation, and this benefit was abrogated by APN blocking. In vitro, the GLP-1 receptor agonist exenatide stimulated APN expression in 3T3-L1 cells. CONCLUSIONS: These results indicate that the DPP4 inhibition-mediated benefits are likely attributable, at least in part, to attenuation of plaque inflammation, oxidative stress and proteolysis associated with GLP-1-mediated APN production in ApoE-/- mice under stress. Thus, DPP4 will be a novel therapeutic target for the treatment of stress-related cardiovascular disease.
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