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Complement components, but not complement inhibitors, are upregulated in atherosclerotic plaques
K Yasojima1, C Schwab, E G McGeer
1Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia, Vancouver.
Insights
Atherosclerotic plaques show complement activation, primarily via the classical pathway. Key complement inhibitors are not upregulated in plaques, suggesting a lack of defense against this inflammatory process.
Area of Science:
- Immunology
- Cardiovascular Biology
- Molecular Medicine
Background:
- Complement activation is implicated in the pathogenesis of atherosclerosis.
- Arterial tissue possesses complement regulatory proteins that can inhibit complement cascade.
- Understanding the balance between complement activation and inhibition in atherosclerotic plaques is crucial.
Purpose of the Study:
- To evaluate the capacity of human atherosclerotic plaques and normal arterial tissue to inhibit complement activation.
- To compare the expression of complement regulators and their targets in plaque versus normal artery.
- To determine the predominant complement pathway activated in atherosclerotic plaques.
Main Methods:
- Analysis of messenger RNA (mRNA) expression for complement inhibitors (C1 inhibitor, decay accelerating factor, CD46, C4BP, CD59) and their targets in plaque and normal arterial tissues.
- Quantitative assessment of mRNA levels using comparative ratios.
- Detection of complement activation markers (Bb fragment of factor B) using Western blotting and immunohistochemistry.
Main Results:
- All evaluated complement inhibitor mRNAs were detected in both plaque and normal arterial tissues, with no significant difference in their expression ratios.
- mRNA levels for C1r, C1s, C4, C7, and C8 were significantly increased in atherosclerotic plaques compared to normal arteries.
- The Bb fragment of factor B, a marker of alternative pathway activation, was minimally detected, indicating limited involvement of this pathway.
Conclusions:
- The classical complement pathway, not the alternative pathway, is predominantly activated in atherosclerotic plaques.
- Despite the presence of complement regulators, they are not upregulated in atherosclerotic plaques to counteract the observed complement activation.
- This imbalance suggests a potential vulnerability of atherosclerotic lesions to complement-mediated damage.
Abstract:
Complement activation occurs in atherosclerotic plaques. The capacity of arterial tissue to inhibit this activation through generation of the complement regulators C1 inhibitor, decay accelerating factor, membrane cofactor protein (CD46), C4 binding protein (C4BP), and protectin (CD59) was evaluated in pairs of aortic atherosclerotic plaques and nearby normal artery from 11 human postmortem specimens. All 22 samples produced mRNAs for each of these proteins. The ratios of plaque versus normal artery pairs was not significantly different from unity for any of these inhibitors. However, in plaques, the mRNAs for C1r and C1s, the substrates for the C1 inhibitor, were increased 2.35- and 4.96-fold, respectively, compared with normal artery; mRNA for C4, the target for C4BP, was elevated l.34-fold; and mRNAs for C7 and C8, the targets for CD59, were elevated 2.61- and 3.25-fold, respectively. By Western blotting and immunohistochemistry, fraction Bb of factor B, a marker of alternative pathway activation, was barely detectable in plaque and normal arterial tissue. These data indicate that it is primarily the classical, not the alternative pathway, that is activated in plaques and that key inhibitors are not upregulated to defend against this activation.