AUTHOR=Lei Yanna , Cui Qingsong , Yang Guang , Piao Limei , Inoue Aiko , Wu Hongxian , Li Xiang , Kuzuya Masafumi , Cheng Xian Wu 

TITLE=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

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=9

YEAR=2021

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.687868

DOI=10.3389/fcell.2021.687868

ISSN=2296-634X

ABSTRACT=<sec><title>Objectives</title><p>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 <italic>E</italic>-deficient (<italic>ApoE</italic><sup>–/–</sup>) mice, with a special focus on glucagon-like peptide-1 (GLP-1)/adiponectin (APN) axis.</p></sec><sec><title>Methods and Results</title><p>6-week-old <italic>ApoE</italic><sup>–/–</sup> mice loaded a high-fat diet were randomly assigned into non-stress (<italic>n</italic> = 12) and stress (<italic>n</italic> = 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<sup><italic>phox</italic></sup>, p47<sup><italic>phox</italic></sup>, gp91<sup><italic>phox</italic></sup>, 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.</p></sec><sec><title>Conclusion</title><p>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 <italic>ApoE</italic><sup>–/–</sup> mice received chronic stress conditions.</p></sec>