Complement-Induced Release of Monocyte Chemotactic Protein-1 From Human Smooth Muscle Cells

Abstract

Increasing evidence suggests that complement activation might represent an important mechanism in early atherogenesis. Thus, complement components, in particular the membrane attack complex (MAC) C5b-9(m), have been isolated from human atherosclerotic lesions. Furthermore, complement activation is known to occur in atherosclerotic lesions induced in experimental animals, and the severity of cholesterol-induced plaques is markedly reduced in complement-deficient animals. During atherogenesis monocytes are recruited into the arterial wall, and a potent chemoattractant for monocytes, monocyte chemotactic protein-1 (MCP-1), is expressed by vascular smooth muscle cells (SMCs). We hypothesized that generation of MACs on SMCs during the activation of complement might lead to the release of MCP-1 and hence to monocyte recruitment. In this study, MACs were generated on human SMCs in vitro by sequential addition of the purified complement components C5b6, C7, C8, and C9. This supernatant of the culture was chemotactic for freshly isolated peripheral blood monocytes in a modified Boyden chamber. The chemotactic activity of the supernatant was abolished by anti-MCP-1 blocking antibodies but not by an isotype-matched antibody against an irrelevant antigen. The release of chemotactic activity was dependent on the dose of MAC formed on SMCs and was demonstrated within 10 minutes of exposure of the cells. The data support the hypothesis that complement-mediated release of MCP-1 from SMCs might be important in the recruitment of monocytes into the developing atherosclerotic lesion and could be an important initiating event in atherogenesis.

Enzymatically Modified Low‐Density Lipoprotein Is Present in All Stages of Aortic Valve Sclerosis: Implications for Pathogenesis of the Disease

“…The significance of local complement activation itself can hardly be overemphasized. Complement plays a role in promoting the progression of cardiovascular disease, for example by acting as a drive to inflammation by increasing secretion of monocyte chemotactic protein‐1 and/or interleukin‐8 34, 35. Possible targets for sublytic complement attack in aortic valve sclerosis are VICs/myofibroblasts, the main cell type of the aortic valve (Figure 6A) 36…”

Complement C6 Deficiency Protects Against Diet-Induced Atherosclerosis in Rabbits

“…In vitro, "bystander" damage by C5b-9 on smooth muscle cells provokes massive release of monocyte chemotactic protein-1. 48 The possibility must also be considered that SC5b-9 complexes, the biological functions of which have not been explored in detail, contribute to lesion progression via unknown mechanisms. 49 The terminal complement sequence may play a detrimental role in human atherosclerosis, so epidemiological analyses on the occurrence and extent of atherosclerosis in subjects deficient in terminal complement components C6-C9 are warranted.…”

Endothelial Nuclear Factor-κB Translocation and Vascular Cell Adhesion Molecule-1 Induction by Complement

“…1,[42][43][44] In addition to causing direct tissue injury, complement may also indirectly mediate vascular injury by stimulating leukocyte activation and chemotaxis and by increasing endothelial leukocyte adhesion molecule expression. 16,17,45 However, the intracellular mechanisms by which the terminal complement components induce endothelial leukocyte adhesion molecule expression are not completely characterized.…”