Statins Mitigate Stress-Related Vascular Aging and Atherosclerosis in apoE -Deficient Mice Fed High Fat-Diet: The Role of Glucagon-Like Peptide-1/Adiponectin Axis.

Objectives: Exposure to chronic psychosocial stress is a risk factor for atherosclerotic cardiovascular diseases. Given that the 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitor statins prevent atherogenesis, we evaluated whether pitavastatin prevents chronic stress- and high fat diet-induced vascular senescence and atherogenesis in apolipoprotein E -deficient ( ApoE ^-/- ) mice, with a special focus on glucagon-like peptide-1 (GLP-1)/adiponectin (APN) axis.
Methods and Results: 6-week-old ApoE ^-/- mice loaded a high-fat diet were randomly assigned into non-stress ( n = 12) and stress ( n = 13) groups for 12 weeks. Non-stress control mice were left undisturbed. Chronic stress accelerated high fat diet-induce arterial senescence and atherosclerotic plaque growth. The chronic stress lowered the levels of circulating GLP-1 as well as adipose and plasma APN. As compared with the stress alone mice, the pitavastatin-treated mice had reduced macrophage infiltration, elastin fragments, and increased plaque collagen volume, and lowered levels of osteopontin, toll-like receptor-2/-4, macrophage chemoattractant protein-1, C-X-C chemokine receptor-4, p47 ^phox , p47 ^phox , gp91 ^phox , cathepsins S, p16, and p21, mRNAs and/or proteins. Pitavastatin increased plasma GLP-1 and APN levels and suppressed matrix metalloproteinase-2/-9 gene expressions and activities in the aortas. Finally, the protective effect of pitavastatin was abrogated by APN blocking.
Conclusion: These findings suggested that the pitavastatin-mediated pleiotropic vasculoprotective effects are likely attributable, at least in part, to the elevation of GLP-1 and APN levels and the inhibition of diet-induced plaque inflammation, oxidative stress, and proteolysis in ApoE ^-/- mice received chronic stress conditions.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2021 Lei, Cui, Yang, Piao, Inoue, Wu, Li, Kuzuya and Cheng.)