Elevated expression of monocyte chemoattractant protein 1 by vascular smooth muscle cells in hypercholesterolemic primates.

Abstract

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 ...

Chemokines in the Pathogenesis of Vascular Disease

“…Early studies reported that MCP-1 is present in macrophage-rich atherosclerotic plaques in humans 22 and primates. 23 Oxidized lipids have long been implicated as mediators of atherosclerosis and foam cell formation. 24 Studies by Cushing et al 25 demonstrated that minimally oxidized low-density lipoproteins (LDLs), but not native LDLs, induced MCP-1 production in vascular wall cells such as endothelial cells and smooth muscle cells.…”

Inflammatory agents regulate in vivo expression of fractalkine in endothelial cells of the rat heart

“…This gene family consists of four subfamilies (CC, CXC, C, and CX3C) whose distinction is based principally on the relative position of the first two highly conserved cysteine residues. Altered expression of chemokines in a variety of diseases, including those of the cardiovascular system, has been established [2][3][4][5][6][7][8][9][10][11][12][13][14]. For instance, the CC chemokine monocyte chemotactic protein-1 (MCP-1) has been implicated in atherosclerosis, having been demonstrated to be present in atherosclerotic plaques [3,4,6].…”

Human Vascular Smooth Muscle Cells Express Receptors for CC Chemokines

“…30 -32 In addition to being secreted by stimulated human macrophages, 33 MCP-1 is also produced by cultured VSMCs and endothelial cells stimulated with cytokines 34 -36 and minimally modified low density lipoprotein. [37][38][39] RANTES and MIP-1␣ expression has also been documented in a range of chronic inflammatory diseases. 5,40 We and others 36,41 have recently demonstrated that RANTES is expressed by stimulated human VSMCs and endothelial cells.…”