TRAIL (tumour necrosis factor-related apoptosis inducing ligand) is most often reported to induce apoptosis in tumour cells. It is expressed in artery walls but its role and regulation in vascular pathologies is little studied.We aimed to measure the effect of genetic deletion of TRAIL on atherosclerosis in a mouse model. TRAIL was mainly expressed in endothelium, smooth muscle cells and macrophages within plaques. The absence of TRAIL in chow and in fat-fed mice led to greater lesion coverage in aortae (8 weeks, % area ± SEM), n = 7–8, 1.24 ± 0.2 (no TRAIL, chow diet) vs. 0.42 ± 0.1, p < 0.01 and 3.4 ± 0.8 (no TRAIL, Western diet) vs. 0.94 ± 0.2, p < 0.01 and larger, smooth muscle cell rich lesions at aortic roots than control mice (8 weeks, mean lesion area/total cross sectional area ± SEM, n = 7–8, 0.17 ± 0.01 (no TRAIL, chow diet) vs. 0.135 ± 0.006, p < 0.05 and 0.36 ± 0.03 (no TRAIL, Western diet) vs. 0.23 ± 0.02, p < 0.05) particularly at early time points. The larger early lesions appeared to be as a result of increased smooth muscle cells in lesions of TRAIL deficient, pro-atherosclerotic animals. We conclude that TRAIL attenuates plaque size at early stages of atherosclerosis.

Despite its major contribution to platelet reactivity, platelet P2Y12 has no effect on early atheroma formation, whereas vessel wall P2Y12 is important in this process. Ticagrelor and clopidogrel effectively reduced platelet reactivity but were unable to inhibit early atherogenesis, demonstrating that these P2Y12 inhibitors may not be effective in preventing early disease.

Genetic, dietary and immune factors contribute to the pathogenesis of atherosclerosis in humans and mice. Complement activation is an integral part of the innate immune defence but also shapes cellular responses and influences directly triglyceride synthesis. Deficiency of Factor B of the alternative pathway (AP) of complement is beneficial in LDLR−/− mice fed a high fat diet. The serum glycoprotein properdin is a key positive regulator of the AP but has not been studied in experimental atherosclerosis. Atherosclerosis was assessed after feeding low fat (LFD) or high fat (HFD) Western type diets to newly generated LDLR−/− ProperdinKO (LDLR−/−PKO) and LDLR−/−PWT mice. Lipids, lymphocytes and monocytes were similar among genotypes, genders and diets. Complement C3, but not C3adesarg, levels were enhanced in LDLR−/−PKO mice regardless of diet type or gender. Non-esterified fatty acids (NEFA) were decreased in male LDLR−/−PKO fed a HFD compared with controls. All mice showed significant atherosclerotic burden in aortae and at aortic roots but male LDLR−/− mice fed a LFD were affected to the greatest extent by the absence of properdin. The protective effect of properdin expression was overwhelmed in both genders of LDLR−/−mice when fed a HFD. We conclude that properdin plays an unexpectedly beneficial role in the development and progression of early atherosclerotic lesions.

Atherosclerosis is a chronic progressive inflammatory disease which manifests in the arterial vascular tree. It is a major cause of cardiovascular morbidity and contributes significantly to mortality in the developed world. Triggers for this inflammatory process are elevated levels of cholesterol, bacterial infection and obesity. The immune response in atherosclerosis is essentially pro-atherogenic, leading to lipid accumulation and cellular changes within the arterial wall. Small-animal models of atherosclerosis are used to study the relevance of candidate factors (cells, genes, diets) in the development and progression of lesions. From a multidisciplinary viewpoint, there are challenges and limitations to this approach. Activation of complement determines or modifies the outcome of acute and chronic inflammation. This review dissects the role of complement in the early development as well as the progressive manifestation of murine atherosclerosis and the advances in knowledge provided by the use of specific mouse models. It gives a critical overview of existing models, analyses seemingly conflicting results obtained with complement-deficient mouse models, highlights the importance of interrelationships between pro-coagulpant activity, adipose tissue, macrophages and complement, and uncovers exciting avenues of topical research.

BackgroundAtherosclerosis in humans and mice has inflammatory, immune and metabolic components. Mice lacking low-density lipoprotein receptor (LDLR(−/−)) may be protected from atherogenesis by some components of the complement system. The serum glycoprotein Properdin is a key amplifier of complement activation. The role of Properdin in atherosclerosis has not yet been studied.MethodologyWe crossed LDLR(−/−) mice with Properdin-knockout mice and examined atherosclerosis in LDLR(−/−) Properdin-knockout (LDLR(−/−)P-KO) mice compared with LDLR(−/−) Properdin-wildtype (LDLR(−/−)P-WT) fed either a low (LFD) or high-fat diet (HFD; Abdiets / The Netherlands) for 12 weeks.ResultsOn LFD, there were no differences in body weight, atherosclerotic burden in aortae and lipid profiles between genotypes (LDLR(−/−)P-KO vs LDLR(−/−)P-WT) or genders. This was not the case in mice fed the HFD. On HFD, % lesion coverage in the aorta was greater in female LDLR(−/−)P-KO mice compared with males (5.06±0.71 % (f) vs 1.44±0.16 % (m), p<0.005, n=4). There was also a greater per cent increase in body weight in female LDLR(−/−)P-KO mice (14.45±1.31 % (f) vs 5.03±2.13 % (m), p<0.01, n=4). Total cholesterol was also 2.4-fold greater in LDLR(−/−)P-KO females than in LDLR(−/−)P-KO males on HFD (1698±44 mg/dl (f) vs 699±188 mg/dl (m), p<0.005, n=4).ConclusionThese data provide preliminary evidence that Properdin may be protective in HFD-induced atherosclerosis in female mice and the mechanism for this observation is currently under investigation.