Aernoud Fiolet

21 General introduction and thesis outline Experimental evidence for the role of interleukin – 1 in atherosclerosis is well established. Interleukin – 1-deficient hypercholesterolemic mice models have decreased atherosclerotic lesion size, lower blood pressure levels, and lower levels of endothelial dysfunction. In particular, these findings were more frequently observed in those that are deprived of vessel wall interleukin – 1 signalling than of those that are deprived of bone marrow interleukin – 1. 54 Carotid atherosclerotic lesions are reduced in animals for which the interleukin – 1 receptor antagonist is exogenously increased, and the expression of adhesion molecules and monocyte chemotactic protein 1 are all reduced in mice lacking interleukin – 1 β . 55,56 Interleukin – 1 β and the interleukin – 1 receptor antagonist are both present in human atherosclerotic lesions. 57 Direct evidence of interleukin – 1b in human atherosclerotic lesions and prognostic information is scarce due to difficulties encountered when measuring levels of the cytokine. The interleukin – 1 receptor antagonist can be measured with greater precision. 51 Claims have been made that increased levels of interleukin – 1 receptor antagonist may correlate with increased interleukin – 1 β activity, making it usable as surrogate marker, though this is controversial. 58 Increased levels of circulating interleukin – 1 receptor antagonist are indeed associated with an increased risk of cardiovascular disease. 59 CAUSALITY IN INFLAMMATORY MEDIATORS AND ATHEROTHROMBOSIS Similar to interleukin – 6, there is evidence of an increased risk of cardiovascular disease when interleukin – 1–binding cytokine levels are increased. These inflammatory mediators—like many inflammatory mediators—lead to downstream production of several acute-phase protein such as pentraxins (e.g., pentraxin 3 and C – Reactive protein) and serum amyloid A proteins. 60 (Figure 2) Increased levels of these acute phase proteins may thus be the direct consequence of increased atherosclerotic inflammation mediated by interleukin – 6 and interleukin – 1. However, many other pathophysiological processes can cause a similar increased expression. Many of these pathophysiological processes have equal important roles in the development of atherothrombosis and consequent complications. Thus, observing an association of elevated levels of circulating inflammatory biomarkers and the risk for cardiovascular disease does not necessary provide new mechanistic insights, but may only affirm established