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Association between complement factor H and proteoglycans in early human coronary atherosclerotic lesions:
Riina Oksjoki1, Hanna Jarva, Petri T Kovanen
1Wihuri Research Institute, Helsinki, Finland.
Insights
Proteoglycans in artery walls bind factor H, a complement inhibitor, potentially preventing complement activation in superficial layers. Deeper layers lack factor H, allowing complement to activate, contributing to atherosclerosis.
Area of Science:
- Cardiovascular Biology
- Immunology
- Atherosclerosis Research
Background:
- Complement activation is implicated in the development of atherosclerosis.
- Understanding the regulation of complement within human coronary atherosclerotic lesions is crucial.
Purpose of the Study:
- To investigate the spatial distribution of the complement inhibitor factor H and complement activation products (C3d, C5b-9) in human coronary atherosclerotic lesions.
- To elucidate the role of arterial proteoglycans in regulating complement activation.
Main Methods:
- Immunohistochemistry was used to localize factor H, C3d, and C5b-9 in different types of atherosclerotic lesions.
- Surface plasmon resonance and affinity chromatography analyzed the binding of factor H to arterial proteoglycans.
- Functional complement assays assessed the inhibitory effect of glycosaminoglycans on complement activation.
Main Results:
- Factor H and C3d were found in the superficial proteoglycan-rich layer of early lesions, while C5b-9 was located deeper where factor H was absent.
- In vitro studies confirmed that arterial proteoglycans bind factor H.
- Glycosaminoglycans demonstrated an inhibitory effect on complement activation induced by modified LDL or foreign surfaces.
Conclusions:
- Arterial proteoglycans may inhibit complement activation in the superficial intima by binding factor H.
- The absence of factor H and proteoglycans in deeper intimal layers may permit complement activation.
- Differential regulation of complement activation exists between the superficial and deep layers of the human coronary artery.
Objective:
Complement activation has been suggested to play a role in atherogenesis. To study the regulation of complement activation in human coronary atherosclerotic lesions, we examined the spatial relationships between the major complement inhibitor, factor H, and the complement activation products C3d and C5b-9.
Methods And Results:
In early lesions (American Heart Association types II and III), factor H was immunohistochemically found in the superficial proteoglycan-rich layer in association with numerous macrophages and C3d, whereas C5b-9 was found deeper in the intima, where factor H was virtually absent. In vitro experiments involving surface plasmon resonance and affinity chromatography analyses demonstrated that isolated human arterial proteoglycans bind factor H, and functional complement assays showed that glycosaminoglycans inhibit the complement activation induced by modified low density lipoprotein or by a foreign surface.
Conclusions:
The present observations raise the possibility that proteoglycans, because of their ability to bind the major complement inhibitor factor H, may inhibit complement activation in the superficial layer of the arterial intima. In contrast, deeper in the intima, where factor H and proteoglycans are absent, complement may be activated and proceed to C5b-9. Thus, the superficial and the deep layers of the human coronary artery appear to differ in their ability to regulate complement activation.