The anti-inflammatory effects of exercise training promote atherosclerotic plaque stabilization in apolipoprotein E knockout mice with diabetic atherosclerosis

Abstract

Physical exercise is the cornerstone of cardiovascular disease treatment. The present study investigated whether exercise training affects atherosclerotic plaque composition through the modification of inflammatoryrelated pathways in apolipoprotein E knockout (apoE−/−) mice with diabetic atherosclerosis. Forty-five male apoE−/− mice were randomized into three equivalent (n=15) groups: control (CO), sedentary (SED), and exercise (EX). Diabetes was induced by streptozotocin administration. High-fat diet was administered to all groups for 12 weeks. Afterwards, CO mice were euthanatized, while the sedentary and exercise groups continued high-fat diet for 6 additional weeks. Exercising mice followed an exercise program on motorizedtreadmill (5 times/week, 60 min/session). Then, blood samples and atherosclerotic plaques in the aortic root were examined. A considerable (P<0.001) regression of the atherosclerotic lesions was observed in the exercise group (180.339±75.613×103µm2) compared to the control (325.485±72.302×103 µm2) and sedentary (340.188±159.108×103µm2) groups. We found decreased macrophages, matrix metalloproteinase-2 (MMP-2), MMP-3, MMP-8 and interleukin-6 (IL-6) concentrations (P<0.05) in the atherosclerotic plaques of the exercise group. Compared to both control and sedentary groups, exercise training significantly increased collagen (P<0.05), elastin (P<0.001), and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) (P<0.001) content in the atherosclerotic plaques. Those effects paralleled with increased fibrous cap thickness and less internal elastic lamina ruptures after exercise training (P<0.05), while body-weight and lipid parameters did not significantly change. Plasma MMP-2 and MMP-3 concentrations in atherosclerotic tissues followed a similar trend. From our study we can conclude that exercise training reduces and stabilizes atherosclerotic lesions in apoE−/− mice with diabetic atherosclerosis. A favorable modification of the inflammatory regulators seems to explain those beneficial effects.

Atherogenesis: hyperhomocysteinemia interactions with LDL, macrophage function, paraoxonase 1, and exercise

“…In nondiabetic Apoe knockout mice, exercise decreased plasma MMP‐9 (degrades collagen, found in macrophages in plaques) and increased TIMP‐1 (inhibits MMP‐2, MMP‐9) while increasing collagen and elastin content of plaques and decreasing plaque size . Consistent with this report, recent reports also indicated that exercise reduces MMPs and increases TIMP‐1, elastin, and collagen levels in the plaque and thereby confers plaque stability and a reduction in lesion incidence and arterial stenosis . All of these improvements correlate with reduction in macrophages in the plaques, implying that exercise can prevent foam cell formation and reduced macrophage motility, the hallmarks of atherogenesis.…”

“…In ApoE knockout diabetic mice, exercise decreases MMP‐2 (degrades collagen, found in SMCs in plaques), MMP‐3 (degrades type II collagen, found in SMCs and macrophages in plaque), and MMP‐8 (degrades collagens, found in macrophages in plaque) levels as well as IL‐6 (expressed by M1 macrophages). Collagen, elastin, and TIMP‐2 (inhibitor of MMP‐2 and MMP‐9) were also increased in parallel with fibrous cap thickness and fewer . In nondiabetic Apoe knockout mice, exercise decreased plasma MMP‐9 (degrades collagen, found in macrophages in plaques) and increased TIMP‐1 (inhibits MMP‐2, MMP‐9) while increasing collagen and elastin content of plaques and decreasing plaque size .…”

“…185 Consistent with this report, recent reports also indicated that exercise reduces MMPs and increases TIMP-1, elastin, and collagen levels in the plaque and thereby confers plaque stability and a reduction in lesion incidence and arterial stenosis. 184,186 All of these improvements correlate with reduction in macrophages in the plaques, 184,186 implying that exercise can prevent foam cell formation and reduced macrophage motility, the hallmarks of atherogenesis. Support for such a hypothesis comes from another recent report that indicated an exercise-mediated enhancement in reverse cholesterol transport.…”

“…Collagen, elastin, and TIMP-2 (inhibitor of MMP-2 and MMP-9) were also increased in parallel with fibrous cap thickness and fewer. 184 In nondiabetic Apoe knockout mice, exercise decreased plasma MMP-9 (degrades collagen, found in macrophages in plaques) and increased TIMP-1 (inhibits MMP-2, MMP-9) while increasing collagen and elastin content of plaques and decreasing plaque size. 185 Consistent with this report, recent reports also indicated that exercise reduces MMPs and increases TIMP-1, elastin, and collagen levels in the plaque and thereby confers plaque stability and a reduction in lesion incidence and arterial stenosis.…”

Influence of flavonoid-rich fruit and vegetable intake on diabetic retinopathy and diabetes-related biomarkers

“…Previous work has confirmed a relationship between dietary flavonoid intake and incidence of diabetes (Bahadoran et al, 2013;Kadoglou et al, 2013); however, to our knowledge, we are the first to show the relationship between flavonoid intake on markers of diabetes severity and retinopathy in U.S. adults with diabetes. Not only was HFVC an independent predictor of diabetes-related biomarkers, but for each 10 U increase in HFVC index, participants had 33% lower odds to have retinopathy.…”