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The complement system in atherosclerosis
1Department of Clinical Chemistry, Sahlgren's Hospital, Gothenburg, Sweden.
Insights
The complement system, a part of immunity, is activated in atherosclerosis and myocardial infarction. Its activation products influence lesion development and heart attack severity.
Area of Science:
- Immunology
- Cardiovascular Biology
- Pathology
Background:
- The complement system is a crucial part of innate immunity, involving plasma proteins, receptors, and regulatory molecules.
- Complement activation culminates in the formation of C5b-9 terminal complexes, implicated in various pathological conditions.
- These complexes have been detected in human atherosclerotic lesions, suggesting a role in the disease.
Purpose of the Study:
- To investigate the role of complement activation in the pathogenesis of atherosclerosis and its complications.
- To explore the effects of complement activation products on lesion development and myocardial infarction outcomes.
- To understand the regulation of complement activation within atherosclerotic lesions.
Main Methods:
- Immunohistochemistry to detect complement complexes (C5b-9) and proteins (C3, C4) in human atherosclerotic lesions and cardiac myocytes.
- In vitro studies using cholesterol and oxysterols to assess their complement-activating properties.
- Experimental models of myocardial ischemia to evaluate the effects of decomplementation on infarct size and inflammation.
Main Results:
- Endothelial cells in atherosclerotic lesions and cardiac myocytes post-myocardial infarction show complement protein deposition (C3, C4, C5b-9).
- Cholesterol and oxysterols can activate the complement system in vitro.
- Experimental reduction of complement (decomplementation) decreased infarct size and inflammatory cell infiltration in a model of myocardial ischemia.
Conclusions:
- The complement system is activated in atherosclerosis and myocardial infarction, playing a role in disease pathogenesis and progression.
- Complement activation products may influence macrophage function and lesion development, though mechanisms require further elucidation.
- Further research is needed to fully understand the complex role and regulation of complement in cardiovascular diseases.
Abstract:
Complement is a term referring to a collection of plasma proteins, specific cellular receptors and cell surface regulatory molecules. Activation of the complement system to completion results in the formation of C5b-9 terminal complexes. These complexes have been observed in human atherosclerotic lesions by immunohistochemistry. Although the structure(s) which activate complement in lesions have not been defined, cholesterol and oxysterols exhibit this property in vitro. Endothelial cell damage leads to complement activation and endothelial cells overlying atherosclerotic lesions have been observed to contain C3 and C5b-9 antigens. Cardiac myocytes stain for complement proteins (C3, C4 and C5b-9) following myocardial infarction. Infarct size and extent of inflammatory cell infiltrates are diminished by decomplementation prior to experimentally-induced myocardial ischemia. Following myocardial infarction and ulceration of atherosclerotic lesions in human patients there is an increase in circulating complement activation products and a decrease in the level of native C1 through C4 proteins. Thus, it appears that complement plays a role in atherogenesis and its sequelae. Little is known however, about the pathophysiological effects complement activation products exert on lesion development, for example through modulation of macrophage functions, or how complement activation is regulated in lesions. Implications for complement in atherogenesis are discussed.