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.

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

doi:10.3389/fcell.2021.687868

Abstract

ObjectivesExposure 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 Results6-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, p47phox, p47phox, gp91phox, 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.ConclusionThese 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.

Highlights

Accumulating evidence indicated that chronic stress is involved in metabolic and inflammatory cardiovascular disorders (Bernberg et al, 2012; Heidt et al, 2014)
Our present study’s findings may contribute to this field, as we observed the following: (a) Chronic stress significantly enhanced the inflammation action and oxidative stress process in ApoE−/− mice fed a high-fat diet, and it increased endothelial senescence, which promoted the development of atherosclerosis. (b) Chronic stress favored the formation of vulnerable plaques by changing the components of the Extracellular matrix (ECM), and it decreased the plaques’ α-SMC content. (c) As expected, the traditional anti-atherosclerosis drug pitavastatin alleviated the progression of atherosclerosis and promoted the TLR-2 TLR-4 CXCR-4 gp 91phox p47phox P67phox cathepsins S (Cat S) MMP-2 MMP-9 APN
The results of the present study demonstrated that chronic (12-week) stress significantly increased the accumulation of macrophages and the expression of osteopontin proteins of atherosclerotic plaques; the stress increased the mRNA levels of TLR2, TLR-4, macrophage chemoattractant protein-1 (MCP-1), and CXCR-4 in the mouse aorta

Summary

Introduction

Accumulating evidence indicated that chronic stress is involved in metabolic and inflammatory cardiovascular disorders (Bernberg et al, 2012; Heidt et al, 2014). The mechanisms underlying chronic stress-related diseases have become a research focus. Most of the evidence suggests that the pathogenic effect of chronic stress is exerted mainly on the hypothalamic-pituitary-adrenal axis and/or the body’s sympathetic nervous system, followed by the induction of disorders such as atherosclerosis (Barik et al, 2013; Cox et al, 2014; Heidt et al, 2014). We conducted the present study to explore the potential mechanisms involved in chronic stress-related atherosclerosis formation, focusing on inflammation and oxidative stress. We investigated whether the traditional anti-atherosclerosis drug pitavastatin can ameliorate this stress-related atherosclerosis and its mechanisms, with a special focus on glucagon-like peptide-1 (GLP-1)/adiponectin (APN) axis

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Results

Discussion

Conclusion