Fatty streak formation, atherosclerosis

Munday, J.S., Thompson, K.G., James, K.A.C. 1999. Dietary conjugated linoleic acids promote fatty streak formation in the C57BL/6 mouse atherosclerosis model. Br. J. Nutr. 81,251-255. 

Kowala MC, Nunnari JJ, Durham SK, Nicolosi RJ (1991) Dox-azin and cholestyramine similarly decrease fatty streak formation in the aortic arch of hyperlipidemic hamsters. Atherosclerosis 91 35—49... 

Kowala, M.C., Nuimari, J J., Durham, S.K., and Nicolosi, R J. (1991) Doxazosin and Cholestyramine Similarly Decrease Fatty Streak Formation in the Aortic Arch of Hyperlipidemic Hamsters, Atherosclerosis 91,35-49. 

In atherosclerosis, ox-LDL is taken up ultimately by macrophages and smooth muscle cells in the arterial intima. Once loaded with lipid, these cells have a foamy appearance when examined histologically. The accumulation of these so-called foam cells in the artery wall leads to the formation of fatty streaks , which can lead to atheromatous plaque formation and consequent coronary heart disease. 

The formation of atherosclerotic plaques is the underlying cause of coronary artery disease (CAD) and ACS in most patients. Endothelial dysfunction leads to the formation of fatty streaks in the coronary arteries and eventually to atherosclerotic plaques. Factors responsible for development of atherosclerosis include hypertension, age, male gender, tobacco use, diabetes mellitus, obesity, and dyslipidemia. 

The atherosclerotic lesions develop in a complex, chronic process. The first detectable lesion is the so-called fatty streak, an aggregation of lipid-laden macrophage foam cells. The next stage of development is the formation of plaques consisting of a core of lipid and necrotic cell debris covered by a layer of connective tissue and smooth muscle cells. These plaques hinder arterial blood flow and may precipitate clinical events by plaque rupture and thrombus formation. Platelets from the thrombi, activated macrophages, and smooth muscle cells release growth factors and cytokines resulting in an inflammatory-fibroproliferative response that leads to the advanced lesions of atherosclerosis. 

Abramovitz, D., Gavri, S., Harats, D., Levkovitz, H., Mirelman, D., Miron, T., Eilat-Adar, S., Rabinkov, A., Wilchek, M., Eldar, M., and Vered, Z. 1999. Allicin-induced decrease in formation of fatty streaks (atherosclerosis) in mice fed a cholesterol-rich diet. Coron. Artery Dis. 10, 515-519. 

There, also, is interest in dietary monounsaturated fatty acids because of their possible protective effect against oxidation of LDL cholesterol (101). There is appreciable evidence that the uptake of LDL cholesterol and the formation of fatty streaks in the intima of large blood vessels, which is considered an early lesion of atherosclerosis, is enhanced by the oxidation of the LDL cholesterol (102, 103). LDL cholesterol was found to be appreciably more stable to oxidation when subjects were fed diets rich in oleic acid than when fed linoleic acid enriched diets (104-106). 

Atherosclerosis involves the formation of lipid-rich plaques in the intima of arteries. The plaques begin as fatty streaks containing foam cells, which initially are macrophages filled with lipids, particularly cholesterol esters. These early lesions develop into fibrous plaques that may occlude an artery and cause a myocardial infarct or a cerebral infarct. Formation of these plaques is often associated with abnormalities in... 

From the point of view of atherosclerosis, the two most important peripheral trafficking pathways are those to the endoplasmic reticulum (ER), where cholesterol is esterified by acyl-CoA cholesterol acyltransferase (ACAT), and to the plasma membrane, where cholesterol can be transferred to extracellular acceptors in a process known as cholesterol efflux (Chapter 20). The former process leads to the massive CE accumulation seen in foam cells [14-16]. The ACAT reaction utilizes primarily oleoyl-CoA, thus ACAT-derived CE is rich in oleate. In contrast, plasma lipoprotein-CE tends to be rich in linoleate. As expected, therefore, the cholesteryl oleatexholesteryl linoleate ratio in foam cell-rich fatty streak lesions — 1.9 — is relatively high [17]. However, the ratio in advanced lesions is only 1.1, suggesting an increase in lipoprotein-CE in advanced atheromata due to poor cellular uptake of lipoproteins or to defective lysosomal hydrolysis following uptake by lesional cells. Further discussion of the cholesterol esterification pathway appears in Chapter 15, and cholesterol efflux, which is an important mechanism that may prevent or reverse foam cell formation, is covered in Chapter 20. 

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. 

The global interest in the role of inflammation in the pathogenesis of atherosclerosis has led to a considerable research effort to understand the role of inflammatory mediators in the disease. Although it seems clear that chemokines play a fundamental role in both the formation of early fatty streak lesions and the subsequent development into more complex lesions, a considerable amount of research is still required before the manipulation of chemokine-chemokine receptor interactions can be considered a viable treatment option in coronary artery disease. 

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