Decay-accelerating factor is expressed on vascular smooth muscle cells in human atherosclerotic lesions.

Abstract

Decay-accelerating factor (DAF) is a constitutively expressed plasma membrane glycoprotein on blood cells and endothelium that inhibits cell surface C3/C5 convertase formation, thus inhibiting complement activation and protecting cells from lysis by the terminal complement components. Using monoclonal anti-DAF antibodies in conjunction with anti-smooth muscle cell (SMC)-specific myosin antibodies, it was found by immunohistochemistry that vascular SMC in advanced human carotid atherosclerotic lesions express DAF antigen. The percentage of DAF-positive SMC ranged from 20 to 60% between different patient samples and SMC DAF expression was limited to SMC in the lesion proper. Normal arterial wall SMC exhibited no DAF-specific immunostaining. Essentially 100% of passaged cultured vascular SMC derived from normal human uterine artery, or from umbilical vein, expressed DAF as assessed by immunocytochemistry. A 68-kD band was observed on SDS-PAGE autoradiograms of DAF-immunoprecipitated radiolabeled cultured SMC extracts. Sensitization of rabbit erythrocytes with DAF-containing SMC extracts conferred protection against complement-mediated hemolysis in normal human serum and the protective effect could be reversed by treatment with anti-DAF antibodies. We conclude that DAF is induced on vascular SMC during atherogenesis and in culture.

Characterization of the decay-accelerating factor gene promoter region.

“…6 High-level DAF expression can protect melanoma cells from complement-mediated cytotoxicity (24) and diminished DAF expression can render lymphocytes of AIDS patients sensitive to complement-mediated injury (30). Up-regulation of DAF may play a role in protection of vascular endothelium from autologous complement-mediated injury during immune reactions (28) and this process may be involved in atherogenesis (31). In ocular tissues, DAF expression provides virtually all of the complement regulatory activity (3) and in the kidney it protects glomerular epithelial cells (32,33).…”

Decay-Accelerating Factor Suppresses Complement C3 Activation and Retards Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

“…63 DAF is not expressed on normal VSMC but can be identified on VSMC as well as macrophages in advanced plaques, and is functionally competent as a complement regulator ex vivo. 64,65 Furthermore, mRNA transcripts for DAF and other complement regulators appear to be proportionately less in plaques than transcripts for complement pathway proteins. 51 This imbalance may be particularly important in allowing complement activation, in view of the limited capacity of the soluble regulator Factor H to penetrate into atherosclerotic lesions.…”

Immune mechanisms in atherosclerosis.

“…78 One of the major functions of macrophages is to participate in the immune response by presenting foreign antigen to T lymphocytes. The macrophage internalizes foreign antigens by endocytosis, partially degrades them in its lysosomes, and then transfers antigen fragments, to the cell surface.…”

“…The assembly of the C5b-9 complex from the C5b, C6, C7, C8, and C9 proteins creates conformational neoantigens that are not present on any of the native components. 78 Antibodies to the neoantigens are specific for the C5b-9 macromolecular complex, and the presence of C5b-9 complexes in a tissue, therefore, indicates that complement activation has taken place. The finding of C5b-9 on fibrillar structures in the fibrous cap and in an amorphous pattern in the lipid core strongly suggests that complement activation is occurring in the plaque.…”

“…77 Further support for the hypothesis that complement activation may play an important role in atherosclerosis was obtained by recent studies of C3-binding proteins in plaques. 78 It was observed that the smooth muscle cells of atherosclerotic plaques (but not of normal arteries) express decay-accelerating factor, which protects the cells from complement-mediated lysis by inhibiting C3/C5 convertase formation. This shows that the phenotypic changes of smooth muscle cells during atherogenesis involve the induction of complement regulatory molecules.…”