Expression of monocyte chemoattractant protein 1 in macrophage-rich areas of human and rabbit atherosclerotic lesions.

Abstract

The recruitment of monocyte-macrophages into the artery wall is one of the earliest events in the pathogenesis of atherosclerosis. Monocyte chemoattractant protein 1 (MCP-1) is a potent monocyte chemoattractant secreted by many cells in vitro, including vascular smooth muscle and endothelial cells. To test whether it is expressed in the artery in vivo, we used Northern blot analysis, in situ hybridization, and immunocytochemistry to study the expression of MCP-1 in normal and atherosclerotic human and rabbit arteries. Northern blot analysis showed that MCP-1 mRNA could be isolated from rabbit atherosclerotic lesions but not from the intima media of normal animals. Furthermore, MCP-1 mRNA was extracted from macrophage-derived foam cells isolated from arterial lesions of ballooned cholesterol-fed rabbits, whereas alveolar macrophages isolated simultaneously from the same rabbits did not express MCP-1 mRNA. MCP-1 mRNA was detected by in situ hybridization in macrophage-rich regions of both human and rabbit atherosclerotic lesions. No MCP-1 mRNA was found in sublesional medial smooth muscle cells or in normal arteries. By using immunocytochemistry, protein was demonstrated in human lesions, again only in macrophage-rich regions. Immunostaining of the serial sections with an antiserum against malondialdehyde-modified low density lipoprotein indicated the presence of oxidized low density lipoprotein and/or other oxidation-specific lipidprotein adducts in the same areas that contained macrophages and MCP-1. We conclude that (a) MCP-1 is strongly expressed in a small subset of cells in macrophage-rich regions of human and rabbit atherosclerotic lesions and (ii) MCP-1 may, therefore, play an important role in the ongoing recruitment of monocyte-macrophages into developing lesions in vivo.The earliest grossly visible atherosclerotic lesion is the fatty streak, characterized by the accumulation of lipid-loaded foam cells in the subendothelial space (1). Many of these foam cells are derived from circulating monocytes (2-4) that have penetrated into the subendothelial space and presumably taken up excess native and/or oxidized low density lipoprotein (LDL) (5-8). Thus, one of the important early events in the pathogenesis of atherosclerosis is the adherence of monocytes to the endothelium, followed by their migration into the subendothelial space (1, 3). The entry between endothelial cells presumably is in response to a gradient of one or more chemotactic factors. Several monocyte chemotactic factors have been described-produced by endothelial cells, by smooth muscle cells, or by macrophages (9-14)-but there is almost no information on which of these are important in vivo. Chemotactic activity may also be derived from the extracellular components of the artery wall. For example, proteolytic peptide fragments from several connective tissue matrix proteins are chemotactic for leukocytes (15)(16)(17). In addition, in vitro-oxidized LDL is chemotactic for circulating monocytes (18) and oxidatively modified LDL isolated ...

Adeno-associated virus vector-mediated interleukin-10 gene transfer inhibits atherosclerosis in apolipoprotein E-deficient mice

“…Therefore, MCP-1 is thought to play an important role in the ongoing recruitment of monocyte-macrophages into developing lesions in vivo. 21 Previously, we 22 and others 21,23 reported enhanced MCP-1 expression in experimental and human atherosclerotic lesions. A role for MCP-1 in the initiation of atherogenesis was demonstrated by knockout mice in which the MCP-1 gene itself or its receptor CCR2 was inactivated.…”

Differential chemokine receptor expression and function in human monocyte subpopulations

“…MCP-1 and its receptor CCR2 are important for initiating the formation of atherosclerotic plaques [13][14][15][16][17][18]. Inflammatory cytokines may result in a CD14 ϩ CD16 ϩ phenotype with impaired CCR2 expression and function, physiologically limiting excessive MCP-1-driven recruitment of monocytes into inflammatory lesions.…”

“…Several knock-out models have revealed a role of the CC chemokine monocyte chemotactic protein-1 (MCP-1) and its receptor CCR2 in monocyte extravasation and formation of atherosclerotic lesions where MCP-1 is detectable and monocyte infiltration is involved in initial foam cell development, progression, and destabilization of plaques [13][14][15][16][17][18][19]. Conversely, macrophage inflammatory protein-1␣ (MIP-1␣), which can act via CCR5 [11,12] is found as a chemotactic chemokine for macrophages in synovial fluid or tissue from rheumatoid arthritis, and in mucosal cells from inflammatory bowel disease [20][21][22].…”

Pravastatin Attenuates Cardiovascular Inflammatory and Proliferative Changes in a Rat Model of Chronic Inhibition of Nitric Oxide Synthesis by Its Cholesterol-Lowering Independent Actions.

“…Increased expression of MCP-1 mRNA or protein has been observed in animals and humans with arteriosclerosis or atherosclerosis (15,16). Importantly, we have recently demonstrated that blockade of MCP-1 activity by administrating a neutralizing anti-MCP-1 antibody prevents the early vascular inflammation and reduced late arteriosclerosis in this model (authors unpublished observations 1999), suggesting the essential role of MCP-1 in the development of vascular remodeling as well as monocyte infiltration.…”