Pathogenesis of Atherosclerosis

The foam cells then form deposits of fat in the intima and media of the blood vessel wall, which are called fatty streaks the early form of plaques. This initiates an inflammatory process, as a result of which even more monocytes are recruited into the sub-intimal space. The proliferation of the smooth muscle cells leads to the thickening of the blood-vessel wall, accumulation of more lipids, and development of a lipid-necrotic nucleus, which is covered with fibrous tissue, forming the fibrous cap of a plaque. The narrowing of the vessel can remain unnoticed by the patient for many years. However, in the course of time, a stable plaque can also become unstable, when activated cells within the plaque secrete matrix proteases, which degrade the fibrous cap (Fig. 5.148). This leads within minutes to rupture and thrombus formation, causing occlusion of blood-vessels and resulting in a heart attack, unstable angina pectoris or a stroke. 

148 Histological preparation of a lipid-containing plaque with a thin fibrous cap in a coronary artery. 

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Ghazalpour A, Doss S, Yang X, Aten J, Toomey EM, Van Nas A, et al. Thematic review series The pathogenesis of atherosclerosis. Toward a biological network for atherosclerosis. J Lipid Res 2004 45 1793-805. 

However, peroxidation can also occur in extracellular lipid transport proteins, such as low-density lipoprotein (LDL), that are protected from oxidation only by antioxidants present in the lipoprotein itself or the exttacellular environment of the artery wall. It appeats that these antioxidants are not always adequate to protect LDL from oxidation in vivo, and extensive lipid peroxidation can occur in the artery wall and contribute to the pathogenesis of atherosclerosis (Palinski et al., 1989 Ester-bauer et al., 1990, 1993 Yla-Herttuala et al., 1990 Salonen et al., 1992). Once initiation occurs the formation of the peroxyl radical results in a chain reaction, which, in effect, greatly amplifies the severity of the initial oxidative insult. In this situation it is likely that the peroxidation reaction can proceed unchecked resulting in the formation of toxic lipid decomposition products such as aldehydes and the F2 isoprostanes (Esterbauer et al., 1991 Morrow et al., 1990). In support of this hypothesis, cytotoxic aldehydes such as 4-... 

Lyons, T.J. (1991). Oxidised low density lipoproteins a role in the pathogenesis of atherosclerosis in diabetes Diabet. Med. 8, 411-419. 

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. 

NO (molecular weight = 30) is small but plays a big role in physiological regulation, not least in the vasculature where its effects were first seen (see Chapter 4). Endothelium-derived relaxation factor (EDRF) was discovered its ability to cause dilatation of vessels by relaxing the arterial muscle layer. Only much later was EDRF discovered to be a gas, nitric oxide. More recent interest in NO is based on the evidence that it is antiatherogenic. The pathogenesis of atherosclerosis is complex but many of the known effects of NO can be implicated in this common and serious condition. 

It is currently believed that the oxidative modification of low density lipoprotein (LDL) is an important initial event in pathogenesis of atherosclerosis [50], LDL peroxidation initiated by... 

Endothelial dysfunction is a critical event in the pathogenesis of atherosclerosis and its clinical manifestations [Mano et al., 1996 Cayatte et al., 1994], It accelerates the development of atherosclerosis and may be one of the earliest... 

Oxidative stress, which has been implicated in the pathogenesis of atherosclerosis,35-36 has been shown to considerably attack lipids, not only in LDL, but also in arterial macrophages.37-38 We have previously shown that lipid-peroxidized... 

Body iron level and iron depletion play an important role in the gender differences seen in death from cardiac disease. There is a better correlation with heart disease mortality in iron levels compared with levels of cholesterol (5). It was found that risk of coronary heart disease (6) and carotid atherosclerosis (7) is associated with increased iron stores. However, impaired endothelium-derived nitric oxide activity may be without overt atherosclerosis in patients with risk factors and may be associated with the presence of atherosclerosis (4). Thus, endothelial dysfunction related to iron activity not only may be an early marker for cardiovascular risk but also may contribute to the pathogenesis of atherosclerosis (2) by the stimulation of low-density lipoproteins (LDL) and membrane lipid peroxidation (I) and may be a key to the understanding of early mechanism in the development of atheroma (7,8). Nakayama et al. (9) showed the role of heme oxygenase induction in the modulation of macrophage activation in atherosclerosis. However, Howes et al. (10) concludes that at the moment, the available evidence on iron hypothesis remains circumstantial. Moreover, Kiechl et al. (7) showed that the adverse effect of iron is hypercholesterolemia, In patients... 

Furthermore, Ang n has been found to contribute to VSMC senescence, which has been implicated in the pathogenesis of atherosclerosis (Kunieda et al. 2006). Cell senescence may promote plaque instability, since loss of VSMCs leads to transformation into a rupture-prone plaque with a thin fibrous cap over the lipid-rich core (Geng and Libby 2002). 

Connor, W.E. 1961. Dietary cholesterol and the pathogenesis of atherosclerosis. Geriatrics. 407 115. 

Experimental atherosclerosis was first successfully induced in rabbits by Saltykow (1908) and Ignatowski (1909). During the following years, various scientists found that dietary cholesterol was the responsible stimulus for development of atherosclerosis. Other species are also susceptible to diet-induced atherosclerosis (Reviews by Kritchevsky 1964 Hadjiinky et al. 1991). A unifying hypothesis of the pathogenesis of atherosclerosis has been proposed by Schwartz et al. (1991). 

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