Abstract
An early event in atherogenesis is the recruitment and infiltration of circulating monocytes and macrophage activation in the subendothelial space. Atherosclerosis subsequently progresses as a unresolved inflammatory disease, particularly in hypercholesterolemic conditions. Although physical exercise training has been a widely accepted strategy to inhibit atherosclerosis, its impact on arterial wall inflammation and macrophage phenotype and function has not yet been directly evaluated. Thus, the aim of this study was to investigate the effects of aerobic exercise training on the inflammatory state of atherosclerotic lesions with a focus on macrophages. Hypercholesterolemic LDL-receptor-deficient male mice were subjected to treadmill training for 8 weeks and fed a high-fat diet. Analyses included plasma lipoprotein and cytokine levels; aortic root staining for lipids (oil red O); macrophages (CD68, MCP1 and IL1β); oxidative (nitrotyrosine and, DHE) and endoplasmic reticulum (GADD) stress markers. Primary bone marrow-derived macrophages (BMDM) were assayed for migration activity, motility phenotype (Rac1 and F-actin) and inflammation-related gene expression. Plasma levels of HDL cholesterol were increased, while levels of proinflammatory cytokines (TNFa, IL1b, and IL6) were markedly reduced in the exercised mice. The exercised mice developed lower levels of lipid content and inflammation in atherosclerotic plaques. Additionally, lesions in the exercised mice had lower levels of oxidative and ER stress markers. BMDM isolated from the exercised mice showed a marked reduction in proinflammatory cytokine gene expression and migratory activity and a disrupted motility phenotype. More importantly, bone marrow from exercised mice transplanted into sedentary mice led to reduced atherosclerosis in the recipient sedentary mice, thus suggesting that epigenetic mechanisms are associated with exercise. Collectively, the presented data indicate that exercise training prevents atherosclerosis by inhibiting bone marrow-derived macrophage recruitment and activation.
Highlights
Atherosclerosis and resulting cardiovascular diseases are major causes of death worldwide (Libby et al, 2019)
The exercise protocol resulted in a reduction in body weight (10%) and epididymal fat pad (40%)
These results demonstrate that aerobic exercise training was effective in counteracting diet-induced systemic inflammation
Summary
Atherosclerosis and resulting cardiovascular diseases are major causes of death worldwide (Libby et al, 2019). Macrophages play crucial roles in all phases of atherosclerosis, including the initiation and progression to advanced lesions Their content and presence at injury sites reflects their capacity for differentiation, proliferation, retention, emigration and death of both resident and macrophages from blood-borne monocytes (Moore et al, 2018). Several other macrophage populations, distinct from the M1 and M2 extremes, likely evoked by the microenvironment stimuli and activation of specific intracellular signaling pathways are present in atherosclerotic lesions, representing a wide spectrum of phenotypes and functions. These macrophages play key roles in lesion initiation, progression, necrosis, remodeling, regression, and resolution (Tabas and Bornfeldt, 2016)
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