Atherosclerosis, implications

Bauriedel G, Schluckebier S, Hutter R, Welsch U, Kandolf R, Luderitz B, and Prescott MF. Apoptosis in restenosis yersus stable-angina atherosclerosis Implications for the pathogenesis of restenosis. Arterioscler. Thromb. Vase. Biol. 1998 18(7) 1132-1139. 

HI. Heinecke, J. W., Oxidants and antioxidants in the pathogenesis of atherosclerosis Implications for the oxidized low density lipoprotein hypothesis. Atherosclerosis 141,... 

Homocysteine has been identified as an independent risk factor for atherosclerosis (32) and thus metaboHc control over homocysteine levels has major health implications. 

PTKs have been implicated in the regulation of a variety of biological responses such as cell proliferation, migration, differentiation, and survival. They have been demonstrated to play significant roles in the development of many disease states, including immunodeficiency, atherosclerosis, psoriasis, osteoporosis, diabetes, and cancer. In recent clinical trials impressive antitumor effects of PTK inhibitors have been observed. In future, PTK inhibitors may therefore become important drugs for the treatment of specific cancers. 

Brown, M.S. and Goldstein, J.L. (1983). Lipxsprotein metabolism in the macrophage implications fiar cholesterol dep>o-sition in atherosclerosis. Ann. Rev. Biochem. 52, 223-261. 

Mechanisms of lipid peroxidation that have been implicated in atherosclerosis may be pertinent to RA. Cellular lipoxygenase enzymes may promote LDL modification by inserting hydroperoxide groups into unsaturated fetty-acid side chains of the LDL complex (Yla-Herttuala etal., 1990). 15-Lipoxygenase has been implicated as an initiator of LDL oxidation (Cathcart etal., 1991) whilst 5-lipoxygenase does not appear to be involved (Jessup et al., 1991). Products of activated lipoxygenase enzymes within inflammatory synovial fluid surest that this pathway could be activated in RA (Costello etal., 1992). 

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. 

This review reports the more recent evidence for the ability of P-carotene and other carotenoids to modulate cell signaling related to cell growth and implicated in a lot of pathological events, including cancer, inflammation, and atherosclerosis by both redox and non-redox mechanisms. 

Several inflammatory conditions including sepsis, atherosclerosis, and Alzheimer s disease are implicated as targets for therapy with TLR4 antagonists based on the presence of pathogen-related or endogenous... 

It should also be mentioned that superoxide and not nitric oxide production by eNOS may have implications for atherosclerosis and septic shock due to imbalance between NO and superoxide formation, for example due to an increase in TNF-a production [164]. These pathophysiological functions of NO synthases will be considered in detail in Chapter 31. 

Fig. 9.1. A dysfunctional or injured endothelium is at the basis for initiation of and progression to atherosclerosis. Several mechanisms, such as adhesion molecules or liberation of von Willebrand factor (vWf, upper panel), determine a series of phenomena, including platelet activation and aggregation. This participation of platelets involves the implication of molecules like glycoprotein Ilb/IIIa, fibrinogen, and von Willebrand factor. The endothelium also acts as a source of signals that regulate local functions, including VSMCs (lower panel). A list of the most relevant messengers produced by a functional and a dysfunctonal endothelium is presented in the lower panel...

K7. Karmansky, I., and Gruener, N., Roles of immobilized proteins and lipoprotein (a) in adhe-sivity of endothelial cells Possible implication for atherosclerosis. Cell Biol. Int. Rep. 16, 503-515 (1992). 

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. 

Although we have discussed briefly the implications of biochemical individuality for alcoholism, for gout, and for arthritis, these are merely examples. A host of other diseases need to be attacked with the same point of view and hold the same promise of success. These include multiple sclerosis, muscular dystrophy, myasthenia gravis, atherosclerosis, essential hypertension, ulcers, diabetes, epilepsy, rheumatic heart disease, nephrosis, liver cirrhosis, congenital heart disease (as well as a host of other malformations which probably involve nutritional deficiencies during fetal life) and even infective diseases such as tuberculosis or poliomyelitis. 

Cantero, A. V., Portero-Otin, M., Ayala, V., Auge, N., Sanson, M., Elbaz, M., Thiers, J. C., Pamplona, R., Salvayre, R., and Negre-Salvayre, A. (2007). Methylglyoxal induces advanced glycation end product (ages) formation and dysfunction of PDGF receptor-beta Implications for diabetic atherosclerosis. FASEB J. 21,3096-3106. 

J.H.F. Rudd, K.S. Myers, S. Bansilal, J. Machac, A. Rafique, M. Farkouh, V. Fuster, Z.A. Fayad, Fluorodeoxyglucose positron emission tomography imaging of atherosclerotic plaque inflammation is highly reproducible Implications for atherosclerosis therapy trials, J. Am. Coll. Cardiol. 50 (2007) 892-896. 

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-... 

Increased production of ET-1 has been implicated in a variety of cardiovascular diseases, including hypertension, cardiac hypertrophy, heart failure, atherosclerosis, coronary artery disease, and myocardial infarction. ET-1 also participates in pulmonary diseases, including asthma and pulmonary hypertension, as well as in several renal diseases. 

For many years, there has been concern by medical professionals and nutritionists over the effects of dietary sugar on human health. Sucrose has been implicated as a cause of juvenile hyperactivity, tooth decay, diabetes mellitus, obesity, atherosclerosis, hypoglycemia, and nutrient deficiencies. 

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