Atherosclerosis Endothelial injuries

Even during the first or second decade of life, small deposits of lipid, fatty streaks, are often detectable in arterial walls. In a study by R. Ross over half of the children (age 10-14) examined at autopsy had fatty streaks in their arteries. These are the first indications of the entry of fat and cholesterol into macrophages in the subendothelial space of an artery. This initiates a sequence of processes that eventually produces a plaque. A prerequisite for the development of fatty streaks, and hence atherosclerosis, is injury to the endothelial cells fining the arterial wall. Many factors are suspected of causing this, including pollutants. 

The oxysterol 7-ketocholesterol is an important COP involved in atherosclerotic lesions and macrophage foam cells (275). There is no direct evidence in humans that COPs contribute to atherogenesis, but it has been found that COP levels are elevated in LDL subfractions that are considered potentially atherogenic (276). In addition, raised levels of 7p-hydroxycholesterol may be associated with an increased risk of atherosclerosis. Arterial injury by COPs causes endothelial dysfunction and arterial wall cholesterol accumulation (277). Even under normocholesterolemic conditions, COPs can cause endothelial dysfunction, increased macromolecular permeability, and increased cholesterol accumulation. These are all factors believed to be involved in the development of atherosclerotic lesions. The atherogenic potential of COPs has been demonstrated by in vitro cell culture (73, 278), as well as in animal feeding studies (279). Japanese quail fed either purified cholesterol or oxidized cholesterol exhibited greater plasma and liver cholesterol concentrations in association with increased severity of atherosclerotic lesions when fed the oxidized cholesterol (279). 

There is experimental evidence that suggests that some oxysterols, but not pure cholesterol, are the prime cause of atherosclerotic lesion formation (162). Upon cholesterol feeding, a strong relationship was seen between plasma oxysterols and aortic wall oxysterols. One may speculate that the deposition of pure lipids, such as cholesterol and its esters, may be merely a secondary process in response to oxysterol-induced endothelial cell injury. Cell injury/dysfunction and the subsequent disruption of endothelial barrier function by oxysterols (163, 164) could initiate the early events in atherosclerosis. Such injury could allow increased uptake... 

Experimental atherosclerosis can be reversed by dietary means. A high-cholesterol, high-fat diet combined with arterial injury produced atherosclerosis in swine22 23 and monkeys.21 The lesions regressed when the animals were removed from the atherogenic diet and placed on a normal diet.22 23 Chronic hyperlipidemia itself may produce the primary endothelial injury that initiates this process of atherosclerosis.24... 

Atherosclerosis is believed to develop by a response to injury mechanism, also referred to as the endothelial injury hypothesis, involving a chain of complex cellular interactions leading to the formation of fatty streaks. 

Oxidized LDL may have several other functions in the development of atherosclerosis, including the expression of chemotactic factors that attract macrophages in the endothelial space, to induce endothelial cells to secrete a chemotactic protein for monocytes activating inflammatory and immune responses, and altering the production of nitric oxide. The endothelial injury... 

The potency of antioxidants to inhibit LDL oxidation in vitro does not correlate with their potency to reduce atherosclerosis in vivo. If functions of antioxidants are due to the protection of LDL from oxidation, water-soluble antioxidants, which are unable to adhere to LDL, may be disadvantageous to protect LDL from oxidation in the subendothelial space. However, epidemiological and animal studies have shown that maiQr water-solifole antioxidants, such as flavonoids, reduce atherosclerosis (5). It is likely that water-soluble antioxidants reduce atherosclerosis by preventing the loss of endogenous lipophilic antioxidants in LDL (mainly a-tocopherol) (11,12). These antioxidants may also prevent endothelial injury causing dyslipidemia and oxidative stress in the circulation. 

Fig. 2. The role of MCP-1 (CCL2)/CCR2 in atherosclerosis is thought to occur through the response of endothelial cells and vascular smooth muscle cells to oxidized lipoproteins. After injury by oxidized lipoproteins, MCP-1 is released and attracts CCR2-expressing monocytes to the site of injury and activates them to secrete inflammatory mediators.

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. 

Figure 22.6 How various factors increase the risk of atherosclerosis, thrombosis and myocardial infarction. The diagram provides suggestions as to how various factors increase the risk of development of the trio of cardiovascular problems. The factors include an excessive intake of total fat, which increases activity of clotting factors, especially factor VIII an excessive intake of saturated or trans fatty acids that change the structure of the plasma membrane of cells, such as endothelial cells, which increases the risk of platelet aggregation or susceptibility of the membrane to injury excessive intake of salt - which increases blood pressure, as does smoking and low physical activity a high intake of fat or cholesterol or a low intake of antioxidants, vitamin 6 2 and folic acid, which can lead either to direct chemical damage (e.g. oxidation) to the structure of LDL or an increase in the serum level of LDL, which also increases the risk of chemical damage to LDL. A low intake of folate and vitamin B12 also decreases metabolism of homocysteine, so that the plasma concentration increases, which can damage the endothelial membrane due to formation of thiolactone.

Our most common lethal disease is atherosclerosis, which causes constriction and blockage of arteries of the heart, brain, and other organs. In the United States, Europe, and Japan half of all deaths can be attributed to this ailment.a,b There seems to be a variety of causes. However, there is agreement that the disease begins with injury to the endothelial cells that form the inner lining of the arteries.3/C/d This is followed by the aggregation of blood platelets at the sites of injury and infiltration of smooth muscle cells, which may be attracted by 12-hydrox-yeicosotetraenoic acid and other chemoattractants formed by activated platelets.c "Foam cells" laden with cholesterol and other lipids appear, and the lesions enlarge to become the characteristic plaques (atheromas). 

Recent evidence suggests that atherosclerosis is a chronic inflammatory process. The recruitment of mononuclear leukocytes and formation of intimal macrophage-rich lesions at specific sites of the arterial tree are key events in atherogenesis. Alterations of chemotactic and adhesive properties of the endothelium play an important role in this process [82]. Quercetin has been reported to inhibit the expression in glomerular cells of monocyte chemoattractant protein-1 (MCP-1) [83] a potent chemoattractant for circulating monocytes. Red wine reduced MCP-1 mRNA and protein expression in abdominal aorta of cholesterol fed rabbits after balloon injury and this effect was associated with a reduced neointimal hyperplasia [84]. The antioxidant-mediated inhibition of nuclear factor k B (NFkB) and the subsequent non selective reduction of cytokine transcription have been suggested to be responsible for these effects [83]. Additionally, quercetin downregulated both phorbol 12-myristate 13-acetate (PMA)- and tumour necrosis factor-a (TNFa)-induced intercellular adhesion molecule-1 (ICAM-1) expression in human endothelial cells [86]. 

As the knowledge of the pathogenesis of atherosclerosis rapidly increases, it appears that an active vascular endothelium, smooth muscle cells, and blood-borne cells such as monocytes and macrophages all play active roles in the atherosclerotic disease process. Risk factors, such as elevated plasma levels of certain lipids, prooxidants, and cytokines, may contribute to the chronic activation/stimulation as well as to the damage of the endothelium and other vascular tissues (160). There is evidence that supports the hypothesis that it is not only pure cholesterol and saturated fats but rather oxidation products of cholesterol and unsaturated fats (and possibly certain pure unsaturated fats) that are atherogenic, possibly by causing endothelial cell injury/dysfiinction. Lipid-mediated endothelial cell dysfunction may lead to adhesion of monocytes, increased permeability of the endothelium to macromolecules, i.e., a decrease in endothelial barrier function, and disturbances in growth control of the vessel wall. 

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