Atherosclerosis mechanisms

Homocysteine arises from dietary methionine. High levels of homocysteiae (hyperhomocysteinemia) are a risk factor for occlusive vascular diseases including atherosclerosis and thrombosis (81—84). In a controlled study, semm folate concentrations of <9.2 nmol/L were linked with elevated levels of plasma homocysteiae. Elevated homocysteine levels have beea associated also with ischemic stroke (9). The mechanism by which high levels of homocysteine produce vascular damage are, as of yet, aot completely uaderstood. lateractioa of homocysteiae with platelets or eadothehal cells has beea proposed as a possible mechanism. Clinically, homocysteine levels can be lowered by administration of vitamin B, vitamin B 2> foHc acid. 

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). 

Vitamin C status is supposed to play a role in immune function and to influence the progression of some chronic degenerative diseases like atherosclerosis, cancer, cataracts, and osteoporosis. The role of vitamin C in immune function, especially during common cold and upper respiratory tract infection, is the subject of lively debate. The exact mechanisms of action have not yet been fully elucidated, but the results of several trials point to a reduced duration and intensity of infections in subjects consuming high amounts of vitamin C (200-1000 mg/d). However, the incidence of common cold was not influenced significantly (24). 

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. 

In atherosclerosis and other heart diseases, the role of carotenoids as antioxidants is probable, but for these types of diseases and also for other degenerative diseases such as cancers, non-antioxidant activities constitute other possible prevention mechanisms. These activities are, for example, stimulation of gap junction communications between cells, and the induction of detoxifying enzymes. The... 

Del Boccio, C., Laprenna, D., Porreca, E., Pennilli, A., Savini, F., Feliciani, P., Ricci, G. and CuccuruUo, F. (1990). Aortic antioxidant defence mechanisms time-related changes in cholesterol fed rabbits. Atherosclerosis 81, 127-135. 

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. 

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). 

Fig. 3. The role of FKN/CX3R1 in inducing atherosclerosis may involve two mechanisms. The first is the release of soluble FKN through cleavage of membrane-expressed FKN by TNF-alpha converting enzyme (TACE). Soluble FKN is then able to attract circulating monocytes and effector T cells expressing CX3CR1. The second mechanism is that of firm adhesion of circulating cells to membrane-bound FKN.

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. 

Platelets play a role in each of the mechanisms of normal hemostasis vasoconstriction, formation of the platelet plug, and blood coagulation. However, they are also involved in pathological processes that lead to atherosclerosis and thrombosis (formation of a blood clot within the vascular system). Antiplatelet drugs interfere with platelet function and are used to prevent the development of atherosclerosis and formation of arterial thrombi. 

The response-to-injury hypothesis states that risk factors such as oxidized LDL, mechanical injury to the endothelium, excessive homocysteine, immunologic attack, or infection-induced changes in endothelial and intimal function lead to endothelial dysfunction and a series of cellular interactions that culminate in atherosclerosis. The eventual clinical outcomes may include angina, myocardial infarction, arrhythmias, stroke, peripheral arterial disease, abdominal aortic aneurysm, and sudden death. 

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