Background: Exposure to psychosocial stress is a risk factor for cardiovascular disease.
Objectives: 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, with a special focus on the pleiotropic effect of adiponectin (APN).
Methods: ApoE–/– mice fed a high-fat (HF) diet were randomly assigned to one of non-stress and immobilized stress groups for 12 weeks (n=15 for each group). Moreover, mice (n=) fed HF diet were divided to 1 of 2 groups and administered vehicle or DPP4 inhibitor anaglipitin (60 mg/kg/day) for 12-weeks under stress conditions (n= 14 for each group).
Results: Quantitative data revealed that chronic stress accelerated vascular senescence and atherosclerotic plaque growth at the aortic root and the thoracic aortas. Stressed mice had increased levels of plasma DPP4 activity and decreased levels of plasma GLP-1 and APN and adipose APN expression. Stress increased plaque microphage 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, 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 (n= 5 for each group). In vitro, the GLP-1 receptor agonist exenatide stimulated APN expression in 3T3 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.