Atherosclerosis lesion development

Fig. 3. (A) Intracellular unesterified cholesterol accumulation in a lesional foam cell. Electron micrograph of the cytoplasm of a foam cell isolated ftom an advanced aortic atherosclerotic lesion in a cholesterol-fed rabbit. The cell was treated with filipin, which forms spicules with unesterified cholesterol. Multiple spicules are observed in vesicles, shown to be lysosomes (depicted by arrows). D , neutral lipid droplet. Bar 0.5 pm. From [34]. Lab. Invest. 41 160-167. (B) Extracellular cholesterol crystals in an advanced atherosclerotic lesion. The section is from the proximal aorta of a fat-fed apolipoprotein E knockout mouse. This mouse model is often used to study atherosclerosis in vivo because the high plasma levels of remnant lipoproteins resulting from absence of apolipoprotein E leads to a much greater degree of atherosclerosis lesion development than observed in wild-type mice. The arrows depict the areas of cholesterol crystals. Reproduced with permission from the publisher.

Atherosclerosis is a progressive vascular fibroproliferative-inflammatory disease. It is triggered, maintained, and driven by risk factors such as hypercholesterolemia, hyperlipidemia, and hypertonus [28]. The characteristic clinical manifestation of atherosclerosis is the atherosclerotic lesion, developing in the vessel wall (atherosclerotic plaque). 

The atherosclerotic lesions develop in a complex, chronic process. The first detectable lesion is the so-called fatty streak, an aggregation of lipid-laden macrophage foam cells. The next stage of development is the formation of plaques consisting of a core of lipid and necrotic cell debris covered by a layer of connective tissue and smooth muscle cells. These plaques hinder arterial blood flow and may precipitate clinical events by plaque rupture and thrombus formation. Platelets from the thrombi, activated macrophages, and smooth muscle cells release growth factors and cytokines resulting in an inflammatory-fibroproliferative response that leads to the advanced lesions of atherosclerosis. 

Atherosclerosis involves the formation of lipid-rich plaques in the intima of arteries. The plaques begin as fatty streaks containing foam cells, which initially are macrophages filled with lipids, particularly cholesterol esters. These early lesions develop into fibrous plaques that may occlude an artery and cause a myocardial infarct or a cerebral infarct. Formation of these plaques is often associated with abnormalities in... 

Kutuk, O. and H. Basaga. 2003. Inflammation meets oxidation NF-kappaB as a mediator of initial lesion development in atherosclerosis. Trends Mol. Med. 9 549-557. 

Much evidence has accrued for a role for inflammation in atherosclerosis. One of the most dramatic demonstrations of this role was the observation in the early 1960s that in cholesterol-fed rabbits given cortisone, no raised lesions developed in spite of higher levels of cholesterol in plasma and in the arterial wall... 

Extensive research has been performed in mice to determine the factors involved in the pathogenesis of atherosclerosis (see Table 6.7). Two knock-out mouse strains were used apolipoprein E (ApoE ) mice that develop spontaneous atherosclerosis that progresses to myocardial infarction and stroke and LDL receptor (Ldlr ) mice that develop hypercholesterolemia and lesion development upon fat feeding [175]. Crossbreeding of this mice with mice that carry deletions in genes of the immune system indicate an essential role of chemokines and their receptors in the early phase of atherosclerosis (for excellent reviews, see [176, 177]). 

The potential of a role by CCL5 in lesion development was recently suggested by Veillard et al. (2004) in a study in which the authors tested the efficacy of the chemokine receptor antagonist met-RANTES in a murine model of atherosclerosis. When recombinant forms of CCL5 are synthesized... 

Some studies have used nonhuman primates to investigate modulation of cholesterol metabolism by vitamin C (see Section 4.1), but none of these studies has assessed the potential of vitamin C to inhibit atherosclerotic lesion development. Finally, a single study has investigated the effect of vitamin C on atherosclerosis in Japanese quail. Morrisey and Donaldson (1979) reported that a combined supplement of vitamins C and E (1 and 0.022 g/kg diet, respectively) had no effect on atherosclerosis in quails fed a cholesterol-containing diet (5-10 g cholesterol/kg diet). 

The first inflammatory stage of atherosclerosis starts early in life with more severe lesions developing only if classical risk factors, especially cholesterol, remain present. Immune responses mounted against antigens cross-react with homologous host proteins in a form of molecular mimicry, for example, HSP are secreted by C. pneumoniae, H. pylori, mammalian vascular cells exposed to stress such as CVD risk factors, and cells within atherosclerotic plaques In addition, serum titers of anti-HSP antibodies are correlated positively with the future risk of CHD, and purified anti-HSP antibodies lyse stressed human EC and macrophages in vitro. Furthermore, immunization with HSP exacerbate athersclerosis in animal models (reviewed in refs. 212,213). However, there is molecular mimicry between epitopes of oxLDL and Streptococcus pneumonia in LDLR -/- mice pneumococcal immunization led to increased IgM levels against oxLDL and decreased the extent of atherosclerosis (214). 

---