Atherosclerosis human studies

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). 

Additionally, human studies of atherosclerosis, mainly located in the carotid ateries and thoratic aorta, with p FlFDO PET were performed. These investigations strengthen the status of p FJEDG PET as noninvasive plaque-imaging technique [191-196]. 

We have attempted to find evidence for gender differences that could alter the information we have provided in this chapter but we could not find reliable human studies in this regard, This does not include differences that may exist in the endothelium or in the coronary artery anatomy or in the pathophysiology of atherosclerosis, but refers to effectiveness of antiplatelet and anticoagulation drugs as compared to the opposite sex. 

Phytosterols are safe when consumed in moderate amounts, such as those used in human studies, lu humans, phytosterol intakes of up to 25 g/d for several mouths were uot associated with adverse health effects. Phytosterol-fortilied foods should be avoided by iudividuals with phytosterolemia, an extremely rare genetic disorder characterized by imusuaUy high rates of intestinal absorption of phytosterols and an increased risk of premature atherosclerosis. ... 

Numerous animal and human studies suggest that dietary cholesterol and certain saturated fatty acids increase serum as well as LDL-cholesterol concentrations. Even though humans with elevated serum cholesterol levels may be at risk, evidence also is mounting to suggest that the complicated processes that occur during atherosclerosis involve not only the participation of modified lipoproteins, but also low level and chronic inflammation and related disorders of the immune... 

The relevance of platelet aggregation in the pathogenesis of atherosclerosis is well documented (Koscielny et al., 1998). The ability of garlic and its metabolites to prevent blood coagulation and platelet aggregation has been well established in numerous in vitro and in vivo (animals and humans) studies (Lawson et al., 1992 Han et al., 1995). 

Shih DM, Reddy S and Lusis AJ (2002). CHD and atherosclerosis human epidemiological studies and transgenic mouse models. In Paraoxonase (PON1) in Health and Disease Basic and Clinical Aspects (LG Costa and CE Furlong, eds), pp. 93-123. Dordrecht, The Netherlands Kluwer Academic Press. 

The calcium exchanged form of the purified natural clinoptilolite (NZ) from the Tasajeras deposit, Cuba, is the active ingredient of a drug designed to reduce total blood cholesterol and prevent atherosclerosis. The study of the Ca -NZ - human bile reaction has revealed that it occurs through the adsorption of three major human bile compounds bile acids, phospholipids and bilirubin. The adsorption of phospholipids on the external surface of the clinoptilolite crystals produces a phospholipids-zeolite interface with anionic activity that allows the adsorption of bile acids. 

Davignon, J., Cohn, J.S., Mabile, L., and Bernier, L. (1999) ApoUpoprotein E and Atherosclerosis Insight from Animal and Human Studies, Clin. Chim. Acta 286,115-143. 

Meagher, E. and Rader, D.J. Antioxidant therapy and atherosclerosis Animal and human studies. Trends Cardiovasc Med. 11, 162-165 (2001). 

Phytosterols (PS) are plant sterols and stanols widely distributed in plant sources that resemble cholesterol in terms of structure and physiological functions. The cholesterol-lowering capacity of PS is well documented in animal and human studies. However, recent studies suggest that the beneficial effects of PS are not only limited to their hypocholesterolemic capacity as they can also act as immunomodulatory, anti-inflammatory, and antidiabetic agents. Further, there is a growing body of evidence which supports that they play an important role in the prevention of other diseases such as cancer and atherosclerosis. Nevertheless, the mechanisms by which PS exert their beneficial functions, the physiological relevance of PS, and their potential adverse effects are not yet fully understood. Therefore, the main aim of this chapter is to provide a contemporaneous overview of the beneficial properties of PS, their mechanism of action, and safety. 

Phospholipid transfer protein (PLTP) (carrier protein that shuttles between lipoproteins to redistribute lipids) deficiency in mice is associated with decreased atherosclerosis despite decreased HDL levels. Two mechanisms are involved decreased Apo B-containing lipoprotein production and levels, and increased antioxidation potential. Human studies indicated that PLTP activity positively correlated with aging, obesity, DM, and CAD (reviewed in ref. 429). PLTP mRNA protein expression and activity was increased by cholesterol loading of macrophages. PLTP increased HDL binding to biglycan, suggesting a role in lipoprotein retention on ECM (430). 

In the first human studies, free non-esterified sitosterol was administered as powder, granules, or liquid suspension with daily intakes of 12-18 g. These studies showed 6-17% decreases in serum cholesterol concentrations with wide individual variations (Farquhar etal, 1956 Kalliomaki etal, 1957 Lees et al, 1977 Schlierf et al, 1978), but resulted in marked increases in plant sterol levels in plasma - especially of campesterol, which is absorbed better than sitosterol. This raised safety concerns in light of the description of sitosterolemia two years previously. Sitosterolemia is a recessively inherited disorder characterized by excessive absorption and high plasma levels of plant sterols, resulting in the premature development of atherosclerosis. 

Experimental evidence in humans is based upon intervention studies with diets enriched in carotenoids or carotenoid-contaiifing foods. Oxidative stress biomarkers are measured in plasma or urine. The inhibition of low density lipoprotein (LDL) oxidation has been posmlated as one mechanism by which antioxidants may prevent the development of atherosclerosis. Since carotenoids are transported mainly via LDL in blood, testing the susceptibility of carotenoid-loaded LDL to oxidation is a common method of evaluating the antioxidant activities of carotenoids in vivo. This type of smdy is more precisely of the ex vivo type because LDLs are extracted from plasma in order to be tested in vitro for oxidative sensitivity after the subjects are given a special diet. 

Depletion of the antioxidant capacity of LDL is an early event in the oxidation process. The main antioxidant in LDL is a-tocopherol, with smaller quantities of 0-carotene and 7-tocopherol also present. The importance of antioxidants in inhibiting the oxidative modification of LDL is su ested by human and animal studies on the prevention of atherosclerosis. Preliminary reports... 

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. 

The expression of 15-LOX in atherosclerotic lesions is one of the major causes of LDL oxidative modification during atherosclerosis. To obtain the experimental evidence of a principal role of 15-LOX in atherosclerosis under in vivo conditions, Kuhn et al. [67] studied the structure of oxidized LDL isolated from the aorta of rabbits fed with a cholesterol-rich diet. It was found that specific LOX products were present in early atherosclerotic lesions. On the later stages of atherosclerosis the content of these products diminished while the amount of products originating from nonenzymatic lipid peroxidation increased. It was concluded that arachidonate 15-LOX is of pathophysiological importance at the early stages of atherosclerosis. Folcik et al. [68] demonstrated that 15-LOX contributed to the oxidation of LDL in human atherosclerotic plaques because they observed an increase in the stereospecificity of oxidation in oxidized products. Arachidonate 15-LOX is apparently more active in young human lesions and therefore, may be of pathophysiological importance for earlier atherosclerosis. In advanced human plaques nonenzymatic lipid peroxidation products prevailed [69],... 

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