Showing papers on "Fatty streak published in 1994"

A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association.

Abstract: The compositions of lesion types that precede and that may initiate the development of advanced atherosclerotic lesions are described and the possible mechanisms of their development are reviewed. While advanced lesions involve disorganization of the intima and deformity of the artery, such changes are absent or minimal in their precursors. Advanced lesions are either overtly clinical or they predispose to the complications that cause ischemic episodes; precursors are silent and do not lead directly to complications. The precursors are arranged in a temporal sequence of three characteristic lesion types. Types I and II are generally the only lesion types found in children, although they may also occur in adults. Type I lesions represent the very initial changes and are recognized as an increase in the number of intimal macrophages and the appearance of macrophages filled with lipid droplets (foam cells). Type II lesions include the fatty streak lesion, the first grossly visible lesion, and are characterized by layers of macrophage foam cells and lipid droplets within intimal smooth muscle cells and minimal coarse-grained particles and heterogeneous droplets of extracellular lipid. Type III (intermediate) lesions are the morphological and chemical bridge between type II and advanced lesions. Type III lesions appear in some adaptive intimal thickenings (progression-prone locations) in young adults and are characterized by pools of extracellular lipid in addition to all the components of type II lesions.

A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association.

Abstract: The compositions of lesion types that precede and that may initiate the development of advanced atherosclerotic lesions are described and the possible mechanisms of their development are reviewed. While advanced lesions involve disorganization of the intima and deformity of the artery, such changes are absent or minimal in their precursors. Advanced lesions are either overtly clinical or they predispose to the complications that cause ischemic episodes; precursors are silent and do not lead directly to complications. The precursors are arranged in a temporal sequence of three characteristic lesion types. Types I and II are generally the only lesion types found in children, although they may also occur in adults. Type I lesions represent the very initial changes and are recognized as an increase in the number of intimal macrophages and the appearance of macrophages filled with lipid droplets (foam cells). Type II lesions include the fatty streak lesion, the first grossly visible lesion, and are characterized by layers of macrophage foam cells and lipid droplets within intimal smooth muscle cells and minimal coarse-grained particles and heterogeneous droplets of extracellular lipid. Type III (intermediate) lesions are the morphological and chemical bridge between type II and advanced lesions. Type III lesions appear in some adaptive intimal thickenings (progression-prone locations) in young adults and are characterized by pools of extracellular lipid in addition to all the components of type II lesions.

Genetic evidence for a common pathway mediating oxidative stress, inflammatory gene induction, and aortic fatty streak formation in mice

Abstract: In a previous survey of inbred mouse strains on an atherogenic diet, we observed that the susceptibility to aortic atherosclerotic lesion formation was associated with the accumulation of lipid peroxidation products, induction of inflammatory genes, and the activation of NF-kB-like transcription factors (Liao, F., A. Andalibi, F. C. deBeer, A. M. Fogelman, and A.J. Lusis. 1993. J. Clin. Invest. 91:2572-2579). We hypothesized that the inflammation-related processes were stimulated by oxidized lipids, since injection of minimally oxidized LDL (MM-LDL) activated the same set of genes. We now report that the induction of inflammatory genes and activation of NF-kB-like transcription factors cosegregate with aortic atherosclerotic lesion formation in BXH recombinant inbred strains derived from parental C57BL/6J (susceptible) and C3H/HeJ (resistant) mice. In addition, the accumulation of hepatic conjugated dienes exhibited a significant correlation with inflammatory gene activation. These results provide strong evidence for the role of inflammatory mediators inducible by oxidative stress in atherogenesis. They also suggest that a major gene contributing to aortic lesion development in this mouse model, designated Ath-1, may control either the accumulation of lipid peroxides in tissues or the cellular responses to such lipid peroxides.

Immune-deficient mice develop typical atherosclerotic fatty streaks when fed an atherogenic diet.

Abstract: Inbred strain C57BL/6J mice develop typical atherosclerotic fatty streaks in the aorta after 15 wk on a high fat, high cholesterol diet. To investigate the effects of the immune system on the development of fatty streaks in this model, C57BL/6J mice with a normal immune system were compared with C57BL/6J mice carrying mutations resulting in various immune deficiencies. These included mice with severe combined immune deficiency, athymic "nude" mice, class I MHC deficient mice, and class II MHC deficient mice. Despite similar lipoprotein profiles, lesion development in the immune compromised strains was similar to or increased compared with normal C57BL/6J mice. Class I MHC deficient mice demonstrated a threefold increase in lesion area (22,961 +/- 6,653 vs 8,868 +/- 1,817 microns2, P = 0.01). Immunohistochemical analysis of lesions showed characteristic features of atherosclerosis with vascular cell adhesion molecule-1 expression, immunoglobulin deposition, monocyte infiltration, and smooth muscle cell proliferation. These data indicate that the classical immune system, while not essential for atherosclerotic fatty streak development, may act to suppress the development of lesions.

Atherosclerosis in genetically obese mice: The mutants obese, diabetes, fat, tubby, and lethal yellow

Abstract: Mice with five different mutations conferring an obese or diabetic phenotype were evaluated for fatty streak lesions after consuming an atherogenic diet containing 15% fat and 1.25% cholesterol (wt/wt) for 14 weeks. The five mutations, fat, obese, tubby, diabetes, and lethal yellow, are maintained as congenic strains with C57Bl 6J (B6) or C57BL KsJ (BKs) as genetic backgrounds. None of the mutants exhibited accelerated fatty streak lesion formation; the mutant fat had aortic lesions comparable in size to those of its control strain, and the mutants obese, diabetes, tubby, and lethal yellow had significantly reduced lesion area in comparison to controls. Although B6 and BKs are closely related strains, we observed that the BKs strain was more prone to early-stage atherogenesis. Fatty streak lesion area was twice as large in BKs mice than those found in B6 mice; likewise, in comparison, the mutants obese and diabetes had larger lesions if they were carried as congenic strains in the BKs rather than the B6 genetic background. Plasma triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and combined low-density and very-low-density lipoprotein cholesterol (LDL-C and VLDL) levels were also measured in the mice. Lipid profiles differed among the mutant mice, but in general, elevations in plasma total cholesterol, triglycerides, and HDL-C were observed. Whereas the hypertriglyceridemia and hypercholesterolemia are consistent with an atherogenic lipid profile, HDL-C levels, which are normally decreased in individuals with non-insulin-dependent diabetes mellitus, were increased in the mouse mutants. The elevated HDL-C levels were apparently sufficient to protect against fatty streak lesion development even in the presence of risk factors such as diabetes, obesity, hypertriglyceridemia, and elevated VLDL and LDL-C levels.

Cell compositions of coronary and aortic atherosclerotic lesions in WHHL rabbits differ. An immunohistochemical study.

Abstract: This study investigated whether coronary atherosclerosis was different from aortic atherosclerosis in Watanabe heritable hyperlipidemic rabbits. Atherosclerotic lesions were immunohistochemically stained by using a monoclonal antibody for rabbit macrophages (RAM-11) and a monoclonal antibody for muscle actin (HHF35) and were also subjected to conventional staining. The areas of the major lesional components, ie, macrophages, smooth muscle cells, collagen fibers, and extracellular lipid deposits, were measured with a color image analyzer. The percent macrophage area in coronary lesions was significantly lower compared with aortic lesions at all stages (early fatty streak, transitional, and advanced), while the percent smooth muscle cell area and collagen area were significantly higher in early fatty streak lesions of the coronary arteries. In addition, the macrophage area/smooth muscle cell area ratio was significantly lower in coronary lesions compared with aortic lesions at all stages. In conclusion, coronary atherosclerosis had a small number of macrophages and was rich in smooth muscle cells, whereas aortic atherosclerosis showed the opposite features. These results suggested that the role of macrophages and smooth muscle cells in the initiation and/or progression of coronary atherosclerosis differs from the role of these cells in aortic atherosclerosis.

Platelets and the lipoproteins: native, modified and platelet modified lipoproteins.

Abstract: Under physiological conditions human blood platelets play a beneficial role in fibrinolysis and regulate the balance with prostacyclin and other factors derived from the endothelium. In response to endothelial injury, adherence of platelets to the denuded arterial surface, platelet aggregation, release of mitogens and subsequent cell proliferation characterize early fibrous plaque lesions. 'Native' atherogenic plasma lipoproteins which are abundant in hypercholesterolemia have been found to play a subtle role in the development of atherosclerosis. In addition, lipoproteins modulate platelet function and alter the susceptibility of platelets to different stimulating agents. The properties of 'modified' atherogenic lipoproteins also seem to be well documented with respect to atherogenesis. After uptake by macrophages, modified atherogenic plasma lipoproteins are thought to contribute to formation of fatty streak lesions. On the other hand, modified atherogenic lipoproteins may directly promote endothelial injury and thus favour enhanced endothelial-platelet interactions. However, the direct effects of modified atherogenic lipoproteins on platelet function have not been revealed in detail. Recent findings have documented that activated platelets themselves may promote modification of atherogenic plasma lipoproteins and thus contribute to enhanced foam cell formation. Therefore stimulation of thrombocytes, and their interaction with native and modified lipoproteins must be considered an important factor in the current concept of atherogenesis.

Mechanisms of atherosclerosis: role of LDL oxidation.

Abstract: There is now extensive evidence suggesting that atherosclerosis begins with the formation of foam cells (the initial stage of the fatty streak) underneath an intact endothelial layer (1). An early step in foam cell formation is the adherence of monocytes to the endothelium overlying an initial accumulation of cholesterol. Subsequently, the monocytes enter the artery wall through cell gap junctions, presumably attracted by a variety of chemoattractants. Within the subendothelial space, monocytes differentiate into macrophages which may then take up lipoproteins (smooth muscle cells may also take up lipoproteins, although to a lesser extent) forming foam cells. The fatty streak, through a series of poorly defined steps, may develop into complex atherosclerotic lesions, called fibrous plaques, which may eventually lead to clinically apparent coronary artery disease (CAD). The fibrous plaques are covered by a thick cap of connective tissue and smooth muscle cells and overlay a core of necrotic cellular debris and lipid. Plaques may eventually grow large enough that they can project into the lumen of the artery, reducing blood flow. Most clinical events, such as myocardial infarctions, appear to be due to ruptures, in the margins of the fibrous plaques, which are macrophage-enriched, leading to hemorrhage into the plaque with subsequent thromboses and acute occlusion of the vessel.

Cell biology of atherosclerosis.

Abstract: UNLABELLED FATTY STREAKS: The precursors of atherosclerotic plaques, fatty streaks, are subendothelial aggregations of lipid-filled macrophages which appear in human arteries within the first decade of life. Some fatty streaks disappear while others progress to fibrous plaques by about the fourth decade. PLAQUE FORMATION The major cells comprising plaques are phenotypically modified, smooth-muscle, monocyte-derived, macrophages and T lymphocytes. The monocyte/macrophages and T lymphocytes are chemoattracted into the vessel wall by substances such as oxidized lipoprotein following their adhesion to a dysfunctional endothelium (caused for example by hyperlipidaemia, hypertension or diabetes). The macrophages and T lymphocytes produce specific matrix-degrading enzymes that initiate smooth muscle phenotypic change to a state in which they are responsive to a vast array of mitogens released by cells within the artery wall and by degranulating platelets. Cytokines also released are mediators of an immune response. These processes result in the formation of a thick fibrous cap of proliferated, phenotypically modified, smooth muscle cells and the extracellular matrix that they have produced, overlying a laterally placed cellular region of macrophages, T lymphocytes and smooth muscle cells and a central core of cell debris and cholesterol which has formed from necrotic, lipid-filled macrophages and smooth muscle cells. THROMBI: Ulceration and splitting of the fibrous cap exposes the highly thrombogenic necrotic core to flowing blood, resulting in thrombi which can travel distally to occlude smaller vessels and produce (dependent on the site of the plaque) myocardial infarction, stroke or gangrene of the extremities.

Atherosclerosis and glycation.

Abstract: Atherosclerosis is the major cause of death in the industrialised world. Though much work on the pathogenesis of atherosclerosis points to 'oxidised' low density lipoprotein (LDL) as a key aetiological feature in the generation of the atherosclerotic plaque, the nature of this 'oxidised' LDL in vivo remains an enigma. We argue here that glycated LDL shows many of the characteristics attributed to 'oxidised LDL' and may be the source of the latter in vivo. These include the increased uptake and impaired degradation of glycated LDL by macrophages and the stimulation of transendothelial chemotaxis of monocytes, cytokine secretion and platelet aggregation. We hypothesise that the covalent binding of glycated LDL to the endothelial cell wall may result in the formation of the early atherosclerotic lesion of the fatty streak and that apolipoprotein E may mediate the physiological clearance of glycated moieties. The proposed role of glycation in the pathogenesis of atherosclerosis would explain its high incidence among diabetics and the contentious epidemiological and experimental correlations between dietary sugar and atherosclerosis.

2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-oxazoles as anti-atherosclerotic agents

Abstract: The earliest lesion of atherosclerosis is development of the fatty streak lesions which contain lipid-laden macrophages and lipid-laden smooth muscle cells. Macrophages do not take up native low density lipoprotein (LDL) but do take up modified, i.e., acetylated LDL or oxidized LDL via acetyl-LDL or "scavenger" receptors to form the foam cells of atherosclerotic plaque. Arterial smooth muscle cells generate superoxide and oxidize LDL in the presence of micromolar concentrations of Cu +2 or Fe +2 . The way LDL can be modified by endothelial cells can be mimicked in vitro by incubation of the lipoprotein in the presence of CuCl 2 . The compounds of this invention inhibit copper mediated oxidation of LDL in vitro and are thus useful in the prophylaxis and treatment of clinical conditions for which inhibition of the oxidative modification of lipids is indicated, for example, atherosclerosis. The compounds of this invention are represented by the formula 1 below ##STR1## wherein: R 1 is hydrogen, C 1 -C 6 alkyl, phenyl or naphthyl; R 2 is OH, NH 2 , OR 3 , or NHCO 2 R 4 wherein R 3 and R 4 are independently selected from C 1 -C 6 alkyl, phenyl or naphthyl; or a pharmaceutically acceptable salt thereof.

Hypertension Treatment and Prevention of New Atherosclerotic Plaque Formation

Abstract: The effect of hypertension on the arterial vascular wall is characterised primarily by morphological changes to the endothelium and hypertrophy of smooth muscle cells within the arterial media. Endothelial dysfunction is manifest through increased permeability to high molecular weight compounds as well as mitogenic and vasoactive substances. At the same time, denudation of the vascular endothelium promotes platelet aggregation and subsequent release of platelet-derived growth factor (PDGF). In conjunction with endothelium- and monocyte-derived growth factors, this mitogen stimulates subintimal smooth muscle cell proliferation and migration and arterial wall thickening, resulting in a haemodynamically important increase in vascular resistance, particularly at the precapillary level. In addition, focal endothelial dysfunction allows entry of lipids into the vascular wall, thereby promoting formation of a lipid-rich fatty streak, the primary ‘early’ atherosclerotic lesion.

Differences in Frequency of Atherosclerosis and Coronary Heart Disease between Populations and Ethnic Groups

Abstract: Human atherosclerosis is a family of lesions that begins in childhood or adolescence and appears with different frequencies in different arterial systems, among different populations. Evidence for a widely varying frequency of coronary atherosclerotic disease is at least half a century old and comes from a variety of sources.

A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association.

Abstract: The compositions of lesion types that precede and that may initiate the development of advanced atherosclerotic lesions are described and the possible mechanisms of their development are reviewed. While advanced lesions involve disorganization of the intima and deformity of the artery, such changes are absent or minimal in their precursors. Advanced lesions are either overtly clinical or they predispose to the complications that cause ischemic episodes; precursors are silent and do not lead directly to complications. The precursors are arranged in a temporal sequence of three characteristic lesion types. Types I and II are generally the only lesion types found in children, although they may also occur in adults. Type I lesions represent the very initial changes and are recognized as an increase in the number of intimal macrophages and the appearance of macrophages filled with lipid droplets (foam cells). Type II lesions include the fatty streak lesion, the first grossly visible lesion, and are characteriz...

Modified low density lipoproteins in the pathogenesis of atherosclerosis.

Abstract: A fatty streak, the earliest atherosclerotic lesion consists mostly of lipid-laden macrophages. The mechanism leading to accumulation of cholestrol ester in macrophages in vivo is unknown, but it may result from the uptake of modified low density lipoproteins that enter from blood or are modified within the arterial wall. In this review I discuss the major types of modified low density lipoproteins with a special focus on their chemical nature.