No abstract

Background — Innate immune reactions against bacteria and viruses have been implicated in the pathogenesis of atherosclerosis. To explore the molecular mechanism by which microbe recognition occurs in the artery wall, we characterized the expression of toll-like receptors (TLRs), a family of pathogen pattern recognition receptors, in atherosclerotic lesions. Methods and Results — Semiquantitative polymerase chain reaction and immunohistochemical analysis demonstrated that of 9 TLRs, the expression of TLR1, TLR2, and TLR4 was markedly enhanced in human atherosclerotic plaques. A considerable proportion of TLR-expressing cells were also activated, as shown by the nuclear translocation of nuclear factor-κB. Conclusion — Our findings illustrate a repertoire of TLRs associated with inflammatory activation in human atherosclerotic lesions, and they encourage further exploration of innate immunity in the pathogenesis of atherosclerosis.

PWRR reinforces PWS as a biomechanical rupture risk index. The ILT has a major impact on AAA biomechanics and rupture risk, and hence, needs to be considered in meaningful FE simulations. The applied FE models, however, could not explain rupture in all analysed aneurysms.

Aneurysm of the abdominal aorta (AAA) is a particular, specifically localized form of atherothrombosis, providing a unique human model of this disease. The pathogenesis of AAA is characterized by a breakdown of the extracellular matrix due to an excessive proteolytic activity, leading to potential arterial wall rupture. The roles of matrix metalloproteinases and plasmin generation in progression of AAA have been demonstrated both in animal models and in clinical studies. In the present review, we highlight recent studies addressing the role of the haemoglobin-rich, intraluminal thrombus and the adventitial response in the development of human AAA. The intraluminal thrombus exerts its pathogenic effect through platelet activation, fibrin formation, binding of plasminogen and its activators, and trapping of erythrocytes and neutrophils, leading to oxidative and proteolytic injury of the arterial wall. These events occur mainly at the intraluminal thrombus–circulating blood interface, and pathological mediators are conveyed outwards, where they promote matrix degradation of the arterial wall. In response, neo-angiogenesis, phagocytosis by mononuclear cells, and a shift from innate to adaptive immunity in the adventitia are observed. Abdominal aortic aneurysm thus represents an accessible spatiotemporal model of human atherothrombotic progression towards clinical events, the study of which should allow further understanding of its pathogenesis and the translation of pathogenic biological activities into diagnostic and therapeutic applications.

The aneurysm wall covered with thrombus is thinner and shows more frequent signs of inflammation, apoptosis of SMCs, and degraded extracellular matrix. These findings suggest that thrombus formation and accumulation of inflammatory cells may perturb the structural integrity and stability of the vessel wall and thereby increase the risk for aneurysm rupture.

The mortality rate of ruptured TAA is high. To decrease this high mortality rate, efficient screening methods for the diagnosis of TAA must be worked out, characteristics indicating high risk of rupture must be identified, and efforts should be made to increase the number of operations for ruptured TAA.

Atherosclerosis is an inflammatory disorder involving complex interactions between vascular wall cells and invading inflammatory cells (14). Genetically modified mouse models of atherosclerosis, based on two pivotal genes of lipid metabolism, i.e., apolipoprotein E (ApoE) and the low-density lipoprotein receptor (LDLR), have been crossed with mice deficient in a specific gene of the LT cascade, e.g., 5-LO and BLT 1 , to investigate the impact of the gene product on the atherosclerotic process (9,(15)(16)(17).In the present study we examined the expression of 5-LO, FLAP, LTA4H, LTC4S, and the receptors BLT 1 , BLT 2 , CysLT 1 , and CysLT 2 in human carotid plaques and aortic lesions from both ApoE (Ϫ͞Ϫ) and compound ApoE (Ϫ͞Ϫ) ϫ LDLR (Ϫ͞Ϫ) mice. In contrast to the mouse models, we find that both 5-LO and LTA4H are expressed at increased levels and colocalize within human atherosclerotic lesions, with expression levels correlating with recent or ongoing symptoms of plaque instability. We also report that a selective inhibitor of LTA4H can block LTB 4 biosynthesis in plaque tissue, thus identifying LTA4H as a potential target for development of drugs for prevention and treatment of atherosclerosis and acute atherothrombotic events. Results Expression of 5LO, FLAP, LTA4H, and LTC4S mRNA in Human CarotidPlaque and Mouse Atherosclerotic Aorta. In the human carotid atherosclerotic lesions, the transcript levels of 5-LO, FLAP, and LTA4H were high, corresponding to a 7.5-fold (7.5 Ϯ 4.1, P Ͻ 0.001), 2.7-fold (2.7 Ϯ 1.3, P ϭ 0.003), and nearly 2-fold (1.9 Ϯ 1.0, P ϭ 0.03) increase relative to normal iliac arteries, respectively (Fig. 1A). In contrast, the levels of LTC4S mRNA were not significantly different from controls.In the ApoE (Ϫ͞Ϫ) mouse aorta, 5-LO and LTA4H mRNA levels were essentially unaltered, whereas FLAP and LTC4S mRNA showed a tendency to increase relative tissue from wild-type C57BL͞6J mice (Fig. 1B). In ApoE (Ϫ͞Ϫ) ϫ LDLR (Ϫ͞Ϫ) mice, the expression pattern of the enzymes was essentially the same as in ApoE (Ϫ͞Ϫ) mice, except that LTA4H mRNA levels were significantly increased (1.7 Ϯ 0.3, P ϭ 0.01) (Fig. 1C). Expression of 5-LO, FLAP, and LTA4H Protein in Human and MouseAtherosclerotic Lesions. Staining of human carotid plaque demonstrated prominent expression of 5-LO, FLAP, and LTA4H in intimal lesion areas that also stained positively for human macrophage marker CD163 (Fig. 2). The distribution of 5-LO,

a rapid increase of thrombus area may be a better predictor of AAA rupture than increase in maximal diameter.