Atherosclerosis pathogenesis

Boyle JJ. Macrophage activation in atherosclerosis pathogenesis and pharmacology of plaque rupture. 

Boyle JJ (2005) Macrophage activation in atherosclerosis pathogenesis and pharmacology of plaque rupmre. Curr Vase Pharmacol 3 63-68... 

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. 

The oxidation hypothesis of atherosclerosis states that the oxidative modification of LDL (or other lipoproteins) is important and possibly obligatory in the pathogenesis of the atherosclerotic lesion thus, it has been suggested that inhibiting the oxidation of LDL will decrease or prevent atherosclerosis and clinical sequelae. LDL oxidation also has important implications for vascular health function. High concentrations of LDL may inhibit arterial function in terms of the release of nitric oxide from the endothelium and many of these effects are mediated by lipid oxidation products. Furthermore, oxidized LDL inhibits endothelium-dependent nitric oxide-mediated relaxations in isolated rabbit coronary arter-... 

Cathcart, M.K. and Folcik, V.A., Lipoxygenases and atherosclerosis protection versus pathogenesis, Free Radical Biol. Med., 28, 1726, 2000. 

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... 

The benefit of glucocorticoid therapy is often limited by several adverse reactions, including cardiovascular disorders such as hypertension and atherosclerosis. Plasma volume expansion due to sodium retention plays a minor role, but increased peripheral vascular resistance, due in part to an increased pressor response to catecholamines and angiotensin II, plays a major role in the pathogenesis of hypertension induced by glucocorticoid excess. However, the molecular mechanism remains unclear. 

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... 

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