Abstract 17649: Exenatide Mitigated Diet-induced Vascular Aging and Atherosclerotic Plaque Growth in ApoE-Deficient Mice under Chronic Stress

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Introduction: Exposure to psychosocial stress is a risk factor for cardiovascular disorders.

Objectives: Given that 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 (n=24) fed the HF diet were assigned to non-stress and immobilized-stress groups for 12 weeks. Moreover, mice (n=22) fed HF diet were divided to 1 of 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 as well as plasma adiponectin (APN) levels and its adipose expression. As compared with the stress-alone mice, the exenatide-treated mice had decreased plaque microvessel density, macrophage accumulation, and broken elastin, enhanced plaque collagen volume, and mitigated the 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 expressions 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 vascular beneficial 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.

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