The collagen cross-linking enzyme lysyl oxidase is associated with the healing of human atherosclerotic lesions.

BACKGROUND: Acute clinical complications of atherosclerosis such as myocardial infarction (MI) and ischaemic stroke are usually caused by thrombus formation on the ruptured plaque surface. Collagen, the main structural protein of the fibrous cap, provides mechanical strength to the atherosclerotic plaque. The integrity of the fibrous cap depends on collagen fibre cross-linking, a process controlled by the enzyme lysyl oxidase (LOX). METHODS AND RESULTS: We studied atherosclerotic plaques from human carotid endarterectomies. LOX was strongly expressed in atherosclerotic lesions and detected in the regions with ongoing fibrogenesis. Higher LOX levels were associated with a more stable phenotype of the plaque. In the studied population, LOX mRNA levels in carotid plaques predicted the risk for future MI. Within the lesion, LOX mRNA levels correlated positively with levels of osteoprotegerin (OPG) and negatively with markers of immune activation. The amount of LOX-mediated collagen cross-links in plaques correlated positively also with serum levels of OPG. CONCLUSIONS: Lysyl oxidase may contribute to the healing of atherosclerotic lesions and to the prevention of its lethal complications. Mediators of inflammation may control LOX expression in plaques and hence plaque stability.

Mycobacterium bovis BCG killed by extended freeze-drying induces an immunoregulatory profile and protects against atherosclerosis.

OBJECTIVES: Atherosclerosis is an inflammatory disease of the arterial wall that leads to myocardial infarction and stroke. Regulatory T cells (Tregs) and IL-10 exert significant anti-atherogenic effects in experimental models of atherosclerosis by modulating vascular inflammation. We have previously shown that Mycobacterium bovis BCG killed by extended freeze-drying (EFD BCG) decreases lung and colon inflammation by recruiting IL-10-producing Tregs. Therefore, the aim of this study was to investigate the effect of EFD BCG on the development of atherosclerosis. DESIGN: We used two strains of atherosclerosis-prone mice: Ldlr(-/-) (four or six EFD BCG injections) and Apoe(-/-) (six injections). RESULTS: In both models, EFD BCG significantly reduced the size of atherosclerotic lesions, increased IL-10 production and reduced the serum levels of pro-inflammatory cytokines (IL-6, IL-13, KC and tumour necrosis factor-α). Shortly after treatment with EFD BCG, the number of plasmacytoid dendritic cells (pDCs) and Foxp3(+) Tregs in the draining lymph nodes increased. EFD BCG also led to accumulation of Tregs, but not of pDCs in the spleen, and reduced activity of NF-κB and increased activity of PPAR-γ in both the spleen and vascular tissue of treated mice. CONCLUSION: EFD BCG has atheroprotective effects through IL-10 production and Treg expansion. These findings support a novel approach to the prevention and treatment of atherosclerosis.