Atherosclerosis is marked by an overt inflammatory infiltrate, with enhanced recruitment of monocytes/macrophages observed in both human and experimental atherosclerosis. We previously determined that monocyte chemoattractant protein 1 (MCP-1) accounts for virtually all of the chemotactic activity produced by vascular (aortic) smooth muscle cells in culture. We now report that arteries from a primate model of atherosclerosis with dietary-induced hypercholesterolemia exhibit increased levels of MCP-1 mRNA expression in vivo, whereas their normal counterparts demonstrate minimal MCP-1 expression. Furthermore, immunohistochemistry and in situ hybridization clearly indicate that the expression of MCP-1 protein and mRNA is in the smooth muscle cells of the medial layer of the artery and in monocytelike and smooth muscle-like cells found in the overlying intimal lesion. These studies indicate that one of the responses to dietary hypercholesterolemia is the expression of MCP-1 by vascular smooth muscle cells. This expression, when augmented with other cellular and molecular factors, could significantly contribute to the recruitment of monocytes/macrophages to the vessel wall.Atherosclerosis is a multistage disease involving invasion of the intima by smooth muscle cells (SMCs) from the media, followed by SMC proliferation and production of an extensive insoluble matrix including such connective tissue components as collagens, elastin, and proteoglycans (1). The two major lesions seen are the fatty streak and the atheromatous or fibrotic plaque. Evidence suggests that fatty streaks, seen in childhood, may progress to fibrotic lesions in adults. Both types of lesions are typified by macrophage invasion (2). Factors released by the macrophage have been shown to influence SMC migration, proliferation, and connective tissue gene expression (3-5). Thus a renewed appreciation of the role of the inflammatory process in coronary arteriosclerosis has emerged.Monocyte chemoattractant protein 1 (MCP-1) is a monomeric polypeptide that migrates in a gel with an estimated molecular mass of 9-15 kDa (6, 7). The various forms of MCP-1 result from differences in O-linked glycosylation and do not affect chemotactic activity (8, 9). Unlike other chemoattractants, MCP-1 is relatively specific for monocytes. Lymphocytes and polymorphonuclear leukocytes lack MCP-1 receptors and do not respond to MCP-1 (10). Previous in vitro studies have shown that this protein can either be secreted by normal cells such as endothelial cells (11) and SMCs (12) or by many tumor cell lines (6, 13). MCP-1 expression in most normal cell types occurs in response to proinflammatory factors such as interleukin 1, tumor necrosis factor a, and interferon y (11, 14). It has also been shown that minimally modified plasma low density lipoprotein stimulates MCP-1 production by human SMCs and endothelial cells in vitro (15). It has been suggested that macrophage/ monocyte recruitment in atherosclerosis occurs in response to a gradient of chemoattractants released ...
Myelin provides important insulating properties to axons allowing for propagation of action potentials over large distances at high velocity. Disruption of the myelin sheath could therefore contribute to cognitive impairment, such as that observed during the normal aging process. In the present study, age-related changes in myelin, myelin proteins and oligodendrocyte proteins were assessed in relationship to calpain-1 expression and cognition in the rhesus monkey. Isolation of myelin fractions from brain white matter revealed that as the content of the intact myelin fraction decreased with age, there was a corresponding increase in the floating or degraded myelin fraction, suggesting an increased breakdown of intact myelin with age. Of the myelin proteins examined, only the myelinassociated glycoprotein decreased with age. Levels of the oligodendrocyte-specific proteins 2¢,3¢-cyclic nucleotide 3¢-phosphodiesterase (CNPase) and myelin/oligodendrocytespecific protein (MOSP) increased dramatically in white matter homogenates and myelin with age. Age-related increases in degraded CNPase also were demonstrable in white matter in association with increases in activated calpain-1. Degraded CNPase was also detectable in myelin fractions, with only the floating fraction containing activated calpain-1. The increases in the activated enzyme in white matter were much greater than those found in myelin fractions suggesting a source other than the myelin membrane for the marked overexpression of activated calpain-1 with age. In addition, CNPase was demonstrated to be a substrate for calpain in vitro. In summary, changes in myelin and oligodendrocyte proteins occur with age, and they appear to have a significant relationship to cognitive impairment. The overexpression of CNPase and MOSP suggests new formation of myelin by oligodendrocytes, which may occur in response to myelin degradation and injury caused by proteolytic enzymes such as calpain. Keywords: aging, calpain, 2¢,3¢-cyclic nucleotide 3¢-phosphodiesterase, monkey, myelin/oligodendrocyte-specific protein, proteolysis. Age-related changes in the subcortical white matter of the brain may play an important role in impairment of cognitive function (Peters et al. 1994(Peters et al. , 1996. Based on volumetric measurements of post-mortem tissue, white matter appears to undergo a generalized shrinkage in size relative to gray matter with age, based on interpolated volume measurements. Comparing young (20-40 years) and old (75-85 years), white matter volume is reduced by 11% compared with a 3% reduction in cerebral cortex in the human (Anderson et al. 1983;Haug and Eggers 1991). Magnetic resonance imaging (MRI) studies have essentially confirmed these earlier studies by showing that only white matter volume decreases with age in the human (Albert 1993). In addition to the reduction in total white matter volume in the aged human brain, there are specific areas of the white matter that show density changes on MRI or computed tomography.These changes, termed leukoaraiosi...
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