DE attenuates arterial thrombosis, reduces lesion size and may promote plaque stability in ApoE-/- mice. The plaque-stabilizing effects of chronic thrombin inhibition might be the result of the favorable modification of inflammatory mechanisms.

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.

Inflammation may contribute to disease progression in arrhythmogenic cardiomyopathy (ACM). However, its role in this process is unresolved. Our goal was to delineate the pathogenic role of the complement system in a new animal model of ACM and in human disease. Using cardiac histology, echocardiography, and electrocardiography, we have demonstrated that the desmin-null mouse (Des-/-) recapitulates most of the pathognomonic features of human ACM. Massive complement activation was observed in the Des-/- myocardium in areas of necrotic cells debris and inflammatory infiltrate. Analysis of C5aR-/-Des-/- double-null animals and a pharmaceutical approach using a C5a inhibitor were used to delineate the pathogenic role of the complement system in the disease progression. Our findings indicate that inhibiting C5aR (CD88) signaling improves cardiac function, histopathology, arrhythmias, and survival after endurance. Containment of the inflammatory reaction at the initiation of cardiac tissue injury (2-3 weeks of age), with consequently reduced myocardial remodeling and the absence of a direct long-lasting detrimental effect of C5a-C5aR signaling on cardiomyocytes, could explain the beneficial action of C5aR ablation in Des-/- cardiomyopathy. We extend the relevance of these findings to human pathophysiology by showing for the first time significant complement activation in the cardiac tissues of patients with ACM, thus suggesting that complement modulation could be a new therapeutic target for ACM.

Aim: To investigate the effects of exercise on atherosclerotic plaque composition, the concentration of matrix metalloproteinases (MMPs) in the atherosclerotic plaque and the systemic circulation. Methods: Ninety apolipoprotein E-deficient (apoE^–/–) mice (45 male) were randomized to the following groups (n = 15 each): control male/female; sedentary male/female; exercise male/female. Mice were kept on a 16-week high-fat diet. Subsequently, the control groups were sacrificed, while the rest of the animals were placed on a normal diet for 6 more weeks. During the latter period, the exercise groups were trained daily on treadmill. At the end of the study, mice were euthanized, and blood samples as well as aortic root specimens were obtained. Results: Compared to control and sedentary animals, exercise training reduced atherosclerotic plaques (–30%; p < 0.01) and increased elastin and collagen content in both genders (p < 0.05). Body weight or lipid profile did not change significantly. Decreased macrophages and MMP-9 as well as increased tissue inhibitor of metalloproteinases 1 (TIMP-1) levels were observed in the atherosclerotic plaques of the exercise-treated groups (p < 0.05). Plasma concentrations of MMP-9 decreased, while plasma TIMP-1 levels increased in the exercise compared to control and sedentary groups (p < 0.05). Conclusions: Exercise training had a favorable effect on the size and composition of the atherosclerotic plaque in apoE^–/– mice, associated with suppressed MMP activity.