Showing papers on "Fatty streak published in 1991"

Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI.

Abstract: Epidemiological surveys have identified a strong inverse relationship between the amount in the plasma of high density lipoproteins (HDL), apolipoprotein AI (ApoA-I), the major protein component of HDL, and the risk for atherosclerosis in humans. It is not known if this relationship arises from a direct antiatherogenic effect of these plasma components or if it is the result of other factors also associated with increases in ApoA-I and HDL levels. Because some strains of mice are susceptible to diet-induced formation of preatherosclerotic fatty streak lesions, and because of available techniques for the genetic manipulation of this organism, the murine system offers a unique setting in which to investigate the process of early atherogenesis. To test the hypothesis that induction of a high plasma concentration of ApoA-I and HDL would inhibit this process, we studied the effects of atherogenic diets on transgenic mice expressing high amounts of human ApoA-I. We report that transgenic mice with high plasma ApoA-I and HDL levels were significantly protected from the development of fatty streak lesions.

The pathogenesis of atherosclerosis: An overview

Abstract: In this unifying hypothesis directed to the etiology and pathogenesis of atherosclerosis, the importance of focal arterial lesion-prone sites has been emphasized. Key initial participants in these sites include the focal intimal influx and accumulation of low-density lipoprotein (LDL) and a preferential recruitment of blood monocytes. Both are further enhanced in the presence of hyperlipidemia, when the quantity of intimal LDL and the oxidative potential of the intima exceed the capacity of macrophages to remove, via the non-down-regulating scavenger receptor, cytotoxic anionic (Ox-LDL) macromolecules. Foam cells, pathognomonic of the fatty streak, form during the receptor-mediated uptake of Ox-LDL by the macrophages. Interstitial free radicals and the excess of Ox-LDL particles injure and kill cells, including the foam cells, with the formation of the necrotic extracellular lipid core, a key transitional step in lesion progression. Monocyte-macrophage recruitment to the intima is likely to be regulated not only by a multiplicity of endothelial adhesive cytokines, integrins, and selectins, but also by the monocyte-specific chemoattractant, MCP-1, constitutively synthesized and secreted by intimal smooth muscle and endothelial cells. Its synthesis and secretion is augmented by mildly oxidized LDL. Free radicals, pivotal in the oxidation of LDL, and derived from activated macrophages, and also endothelial and smooth muscle cells. Smooth muscle cells migrate from the media through the intimal endothelial layer (IEL) and proliferate under the regulation of a number of mitogens, including platelet-derived growth factor (PDGF). Collagen synthesis by smooth muscle cells is substantial. Lymphocytes, as a source of interferons, invade the plaque and are present in the adventitia in substantial numbers, likely representing an autoimmune response in the later stages of plaque development. Platelets and mural thrombosis directly contribute to subsequent plaque growth, particularly after plaque rupture or fissure and disruption of the thromboresistant endothelial cells (EC). Plaque regression in all likelihood involves the conversion of the inert pool of extracellular lipid to a metabolically active intracellular pool and subsequent clearance by the high-density lipoprotein mediated reverse cholesterol transport system. The atherogenic cascades so described conceptually represent arterial inflammatory and healing processes occurring in a hyperlipidemic environment. Many components of pathogenesis are the targets for modulation by genetic, hemodynamic and selected risk factors. The prevention and treatment of the disease should logically target reduction in plasma LDL levels, the inhibition of the oxidative modification of lipoproteins, including LDL, by free radical scavengers, and augmentation of the reverse cholesterol transport system.

Neointima formation impairs endothelial muscarinic receptors while enhancing prostacyclin-mediated responses in the rabbit carotid artery.

Abstract: The purpose of this study was to determine whether the generation of a neointima, an early step in the development of atherosclerosis, affects endothelium-dependent or -independent vasodilation. The neointima was induced, within 7 days, by positioning a nonocclusive silicone collar around one carotid artery in rabbits. After 1, 2, 7, or 14 days segments were cut from the collar-surrounded region of this artery as well as from the sham-operated contralateral artery and were used for isometric tension recording or for bioassay of nitric oxide (NO). The acetylcholine-induced release of NO was significantly reduced at 7 days. The tension recordings suggested that this already occurred at the earliest stages of neointima formation. Neither the capacity of the endothelial cells to form NO in response to the calcium ionophore A23187 nor the capacity of the underlying smooth muscle cells to relax in response to sources of exogenous NO (3-morpholinosydnonimine and nitroglycerin) was affected by the neointima. Therefore, the impaired endothelium-dependent relaxations to acetylcholine are presumably due to a defect at the level of the endothelial muscarinic receptors. The presence of a fully developed neointima did not alter the responsiveness to isoproterenol and forskolin but enhanced prostacyclin-mediated responses (assessed by iloprost and 13-hydroxyoctadecadienoic acid). These results illustrate selective alterations of endothelial and smooth muscle cell function in intima generation before fatty streak formation.

Three-dimensional cytoarchitecture of normal and atherosclerotic intima of human aorta.

Abstract: The three-dimensional cytoarchitecture of normal and atherosclerotic intima of human aorta was studied by light microscopy of consecutive en face preparations (Hautchen preparations) and by scanning electron microscopy. In unaffected intima, a three-dimensional network consisting of cells of variable shape and probably origin was demonstrated. Cellular shape changed from predominantly stellate in the luminal regions of the elastic-hyperplastic layer to elongated spindlelike cells in the musculoelastic layer of the intima. In the surface layers of the fatty streak, cellular contacts were severed, and lipid droplets were often seen between cellular processes. Along with stellate and elongated cells, the fatty streak also had a number of round monocytelike cells. Lipid inclusions were usually detected in stellate and ovoid cells. The integrity of the cellular network was preserved at the marginal zone of the atherosclerotic plaque, while at the slopes and in the central part of the plaque, cells practically lost all contact with each other. Giant stellate cells embedded in crude fibrillar connective tissue matrix were often found there. Disintegration of the cellular network during atherosclerosis is suggested to play an important role in the development of various lesions.

Oxidants, antioxidants and cardiovascular disease.

Abstract: Basic and clinical studies in the past decade suggest an involvement of oxygen-derived free radicals in some cardiovascular diseases including atherosclerosis and hypertension. In atherogenesis evidence indicates that low-density lipoprotein/cholesterol must be oxidized before it can be taken up by the monocytes/macrophages to form foam cells which contribute to the characteristic fatty streak. Free radicals are considered responsible for this oxidation. Population studies reveal that hypertensive patients generally have a lower intake of ascorbic acid and possibly other antioxidants. Ascorbic acid deficiency may lead to defective vasodilation and increased blood pressure due to destruction of certain endothelium-dependent relaxing factors by free radicals. Further studies in this area appear justified.

The Participation of the Complement System in Atherosclerotic Vascular Disease

Abstract: Atherosclerosis is a vascular disease of large and medium-sized arteries wherein the tunica intima becomes thickened due to lipid accumulation, mostly cholesterol and its esters, smooth muscle cell proliferation, and increased deposition of connective tissue matrix. A major risk factor in the development of this disease is hypercholesterolemia arising from elevated levels of low density lipoproteins (LDL). The earliest recognizable lesion, which may be a precursor to the fibrofatty plaque, is the fatty streak. It is predominantly composed of monocyte-derived macrophage foam cells, i.e. cells ladened with intracellular lipid droplets. Hence, a fundamental aspect of atherogenesis is the insudation and accumulation of LDL-derived cholesterol and the attempt by monocyte/macrophages to clear it from the arterial wall. As lesion development progresses, the lipid component becomes surrounded by a fibrotic cap laid down by vascular smooth muscle cells. The proliferation of smooth muscle cells and induction of connective tissue synthesis is probably driven, at least in part, by the products released from resident macrophages. This chapter outlines the participation of the complement system in atherosclerosis. The ability of complement activation products to mediate proinflammatory functions of macrophages implicates this system in the pathogenesis of atherosclerotic lesion development.

Participation of Leukocytes in the Development of Experimentally Induced Arteriosclerotic Lesions — Morphological and Functional Aspects

Abstract: The occurrence of different types of leukocytes including monocytes, lymphocytes and granulocytes, during the development of atherosclerotic lesions has been numerously reported in both man and animal models [4–6, 13–16, 21, 24, 25, 27]. Various aspects of the possible involvement of these leukocytes in atherogenesis were discussed: e.g., the lipid-scavenging function ofmonocytes/macrophages [2, 26, 29] and their putative roles in stimulating smooth muscle cell proliferation [7, 8, 22, 23], or the influences of T lymphocytes on growth properties of myocytes [9, 10]. However, it is still impossible to formulate a comprehensive concept on the roles that leukocytes play in the different phases of plaque development.