doi: 10.1161/01.ATV.0000083385.98775.6D
© 2003 American Heart Association, Inc.
Letter to the Editor |
Association of Complement Inhibitors With Connective Tissue Matrix in Atherosclerotic Lesions
University of Maryland, School of Medicine, Department of Pathology, Baltimore, Md
To the Editor:
We read with great interest the article by Oksjoki et al1 regarding association between complement Factor H and proteoglycans in early human coronary atherosclerotic lesions. We would like to add several comments to this recently published article.
Several studies have demonstrated the presence of terminal complement complex C5b-9 in human atherosclerotic arteries.2–4 Quantitative determination in the human aorta by ELISA showed that C5b-9 levels were highest in intimal thickening and with detectable levels in both normal and fatty streaks intima.5 Our data indicate that activation of complement starts early during the prelesional stages of the atherosclerotic process. The activation is more intense in initial stages than in advanced fibrous plaques. Similar prelesional C5b-9 deposition was found in experimental atherosclerosis.6 In contrast to these findings, Oksjoki et al1 show that C5b-9 was immunohistochemically absent in grossly normal human coronary artery. This difference in the results might be explained by the higher sensitivity of the ELISA for C5b-9.
We have previously examined the relationship between C5b-9 and the complement inhibitor S-protein/vitronectin.7 S-protein/vitronectin prevents C5b-9 insertion in the cell membrane by binding to C5b-7. The formed SC5b-9 complex is cytolytically inactive. Using immuno-electron microscopy, S-protein/vitronectin was localized in association with elastin fibers, collagen bundles, and cell debris in the vicinity of elastin.7 Cell debris embedded in collagen matrix were S-protein/vitronectin negative. In contrast, all cell debris were positive for C5b-9 deposits. These data suggested that connective tissue matrix by associating S-protein/vitronectin play an important role in regulation of terminal complement pathway in atherosclerotic wall. Because C5b-9 deposits are not always associated with S-protein/vitronectin, the inhibition of terminal pathway activation seems to be only partially effective.
Oksjoki et al1 extend our previous observation demonstrating an association between another complement inhibitor, factor H and a connective tissue matrix component, versican proteoglycan. In the deeper parts of the intima, they found C5b-9 deposits in the absence of factor H. Because the immunostaining does not distinguish between membrane inserted C5b-9 and SC5b-9, it is possible that some of the staining seen in the deep layers of human coronary artery may represent cytolytically inactive SC5b-9. The C5b-9 complex was also colocalized with macrophages and smooth muscle cells in the atherosclerotic arterial wall.8,9
Association of C5b-9 with cellular plasma membrane can induce mitogenesis of aortic smooth muscle cells.10 These data suggest that complement inhibitors associated with connective tissue matrix play a regulatory role for complement activation in the arterial wall. Despite the presence of inhibitors, full complement activation is achieved, indicating that complement system and C5b-9 assembly play an important role in the inflammatory pathogenesis of atherosclerosis.
References
1. Oksjoki R, Jarva H, Kovanen PT, Laine P, Meri S, Pentikainen MO. Association between complement factor H and proteoglycans in early human coronary atherosclerotic lesions: implications for local regulation of complement activation. Arterioscler Thromb Vasc Biol. 2003; 23: 630–636.
2. Niculescu F, Rus H, Cristea A, Vlaicu R. Localization of the terminal C5b-9 complement complex in the human aortic atherosclerotic wall. Immunol Lett. 1985; 10: 109–114.[CrossRef][Medline] [Order article via Infotrieve]
3. Niculescu F, Rus HG, Vlaicu R. Immunohistochemical localization of C5b-9, S-protein, C3d and apolipoprotein B in human arterial tissues with atherosclerosis. Atherosclerosis. 1987; 65: 1–11.[CrossRef][Medline] [Order article via Infotrieve]
4. Torzewski M, Klouche M, Hock J, Messner M, Dorweiler B, Torzewski J, Gabbert HE, Bhakdi S. Immunohistochemical demonstration of enzymatically modified human LDL and its colocalization with the terminal complement complex in the early atherosclerotic lesion. Arterioscler Thromb Vasc Biol. 1998; 18: 369–378.
5. Niculescu F, Hugo F, Rus HG, Vlaicu R, Bhakdi S. Quantitative evaluation of the terminal C5b-9 complement complex by ELISA in human atherosclerotic arteries. Clin Exp Immunol. 1987; 69: 477–483.[Medline] [Order article via Infotrieve]
6. Seifert PS, Hugo F, Hansson GK, Bhakdi S. Prelesional complement activation in experimental atherosclerosis. Terminal C5b-9 complement deposition coincides with cholesterol accumulation in the aortic intima of hypercholesterolemic rabbits. Lab Invest. 1989; 60: 747–754.[Medline] [Order article via Infotrieve]
7. Niculescu F, Rus HG, Porutiu D, Ghiurca V, Vlaicu R. Immunoelectron-microscopic localization of S-protein/vitronectin in human atherosclerotic wall. Atherosclerosis. 1989; 78: 197–203.[CrossRef][Medline] [Order article via Infotrieve]
8. Torzewski M, Torzewski J, Bowyer DE, Waltenberger J, Fitzsimmons C, Hombach V, Gabbert HE. Immunohistochemical colocalization of the terminal complex of human complement and smooth muscle cell alpha-actin in early atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 1997; 17: 2448–2452.
9. Rus HG, Niculescu F, Vlaicu R. Co-localization of terminal C5b-9 complement complexes and macrophages in human atherosclerotic arterial walls. Immunol Lett. 1988; 19: 27–32.[CrossRef][Medline] [Order article via Infotrieve]
10. Niculescu F, Badea T, Rus H. Sublytic C5b-9 induces proliferation of human aortic smooth muscle cells: role of mitogen activated protein kinase and phosphatidylinositol 3-kinase. Atherosclerosis. 1999; 142: 47–56.[CrossRef][Medline] [Order article via Infotrieve]
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