Atherosclerosis lesions

Various adhesion molecules are reported to be expressed on vascular endothelial cells at sites of inflammation (Libby, 2002). In fact, VCAM-1, expressed on the surface of vascular endothelial cells in response to inflammatory stimuli, is suggested to play an important role in leukocyte recruitment (Gerrity et al, 1979). The adhesion of monocytes to vascular endothelial cells is the first critical step in the induction of atherosclerosis (Glass and Witztum, 2001). Supportively, the expression of VCAM-1 is reported to increase in atherosclerosis lesions (Cybulsky and Gimbrone,... 

Using MALDI-MSI-based histopathologic examination, Zaima et al. (29) identified and visualized specific markers for aortic atherosclerosis lesions in mice ApoE and in human. They found the same distribution in mice and human samples, in several molecules cholesterol linolate, cholesterol oleate, and phosphatidylcholine. The triacylglycerol only appeared in human... 

Neutrophils are very rarely found in early atherosclerosis lesions [17] but a recent study demonstrated that oxidised LDL may activate T cells in atherosclerotic lesions [34]. 

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.

Early atherosclerosis lesions evaluation Thickness (mm) Surface area (mm /mm)xl000 ... 

Donates statistical significance between groups A and B (p < 0.05), according to Mann-Whitney U-test. Table 7. Assessment of early atherosclerosis lesions observed in rabbit aortas. 

Development of a laboratory animal model that gets coronary atherosclerosis lesions comparable to those of the human and in a manner similar to man ... 

Probucol. Probucol is an antioxidant that is effective in lowering LDL cholesterol. Whereas probucol was known to lower cholesterol after relatively simple clinical trials (160), its mechanism of action as an antioxidant in the treatment of atherosclerosis is quite novel. Probucol has been shown to have the abiUty to produce regression of atherosclerotic lesions in animal models (161). Probucol therefore represents a novel class of pharmaceutical agent for the treatment of atherosclerosis. This effect occurs mechanistically, in part, by preventing oxidation of LDL, a necessary step in foam cell formation. This antioxidant activity has been shown in laboratory experiments and its activity in lowering LDL cholesterol in human studies is well documented (162). 

Atherosclerotic lesion l Monocyte recruitment l Progression of atherosclerosis... 

PPARa Liver, heart, skeletal muscle, atherosclerotic lesions TG- and LDL-C-lowering and HDL-C-raising re-directs excess cholesterol from the peripheral tissues to the liver for excretion into the bile via HDL-C slowed progression of atherosclerosis Fatty acids, eico-sanoids (fatty acids derived from FAS ) Fibrates fenofibrate (Tricor ), genfibrozil (Lopid ) Dyslipidemia... 

PPARy White adipose tissue, atherosclerotic lesions Insulin-sensitizing and glucoselowering re-directs TG from non-adipose tissues and visceral adipose depots for storage in subcutaneous adipose tissue slowed progression of atherosclerosis Fatty acids, eico-sanoids Th iazolid i ned iones pioglitazone (Actos ), rosiglita-zone (Avandia ) Type 2 diabetes, (insulin resistance, metabolic syndrome)... 

The chemical adducts formed by reaction of aldehydes with lysine residues form highly immunogenic epitopes, and antibodies have been prepared specific for malondialdehyde- and 4-hydroxynonenal-conjugated LDL (Gonen et al., 1987 Yla-Herttuala et al., 1989 Jurgens et al., 1990). These antibodies cross-react with material in atherosclerotic lesions but not normal tissue, thus supporting the central role of lipid peroxidation in the patho nesis of atherosclerosis (Yla-Herttuala et al., 1989, 1991). 

It appears then that both intracellular and extracellular antioxidants may be important in the prevention of atherosclerosis. The progression of a lesion may signify that these protective pathways are overwhelmed. 

The earliest recognizable lesion of atherosclerosis is the fatty streak, an a egation of lipid-rich macrophages and... 

Although atherosclerosis and rheumatoid arthritis (RA) are distinct disease states, both disorders are chronic inflammatory conditions and may have common mechanisms of disease perpetuation. At sites of inflammation, such as the arterial intima undergoing atherogen-esis or the rheumatoid joint, oxygen radicals, in the presence of transition-metal ions, may initiate the peroxidation of low-density lipoprotein (LDL) to produce oxidatively modified LDL (ox-LDL). Ox-LDL has several pro-inflammatory properties and may contribute to the formation of arterial lesions (Steinberg et /., 1989). Increased levels of lipid peroxidation products have been detected in inflammatory synovial fluid (Rowley et /., 1984 Winyard et al., 1987a Merry et al., 1991 Selley et al., 1992 detailed below), but the potential pro-inflammatory role of ox-LDL in the rheumatoid joint has not been considered. We hypothesize that the oxidation of LDL within the inflamed rheumatoid joint plays a pro-inflammatory role just as ox-LDL has the identical capacity within the arterial intima in atherosclerosis. 

The Vascular Lesion in Diabetes 183 5.3 Free Radicals and Atherosclerosis 191... 

Boring L, Gosling J, Cleary M, Charo IF. Decreased lesion formation in CCR2 / mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 1998 394 894-7. 

Evidence implicating CX3CR1 and fractalkine in atherosclerosis is growing. Immunohistochemical analysis of human atherosclerotic lesions demonstrate that macrophages in the intima as well as smooth muscle cells, mononuclear cells, and foam cells in the deep intima and media express CX3CL1, whereas normal arteries do not (57,58). 

Growing clinical data also points to the importance of IL-8 in atherogenesis. IL-8 has been found in atheromatous lesions from patients with atherosclerotic disease including carotid artery stenosis (103), CAD (118), abdominal aortic aneurysms (AAA) (103,104,114), and peripheral vascular disease (PVD) (104). Furthermore, studies using plaque explant samples have yielded more direct evidence for IL-8 involvement. Media from cultured AAA tissue induced IL-8-dependent human aortic endothelial cell (HAEC) chemotaxis (122). Homocysteine, implicated as a possible biomarker for CAD, is also capable of inducing IL-8 (123-125) by direct stimulation of endothelial cells (123,124) and monocytes (125). When patients with hyperhomocysteinemia were treated with low-dose folic acid, decreases in homocysteine levels correlated with decreases in IL-8 levels (126). Statins significantly decrease serum levels of IL-6, IL-8, and MCP-1, as well as expression of IL-6, IL-8, and MCP-1 mRNA by peripheral blood monocytes and HUVECs (127). Thus, IL-8 may be an underappreciated factor in the pathogenesis of atherosclerosis. 

---