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Regulation of complement membrane attack complex formation in myocardial infarction
1Department of Bacteriology and Immunology, University of Helsinki, Finland.
Insights
The complement system attacks injured heart tissue in myocardial infarction. This involves complement membrane attack complex (MAC) deposition and reduced CD59 expression, suggesting a mechanism for clearing damaged cardiac cells.
Area of Science:
- Immunology
- Cardiovascular Pathology
Background:
- The complement (C) system, crucial for immune defense, is implicated in myocardial infarction (MI) tissue injury.
- The precise mechanisms triggering complement activation against autologous heart tissue in MI remain unclear.
Purpose of the Study:
- To investigate the expression of complement regulators and deposition of complement components in normal versus infarcted human myocardium.
- To elucidate the role of the complement system in the pathogenesis of MI-induced cardiac tissue damage.
Main Methods:
- Immunofluorescence microscopy was used to detect complement membrane attack complex (MAC) deposits.
- Transmission electron microscopy identified MAC-like structures in infarcted myocardium.
- Expression levels of complement regulators (CR1, DAF, MCP, CD59, C8 binding protein) and deposition of plasma regulators (C4b binding protein, vitronectin) were analyzed.
Main Results:
- Deposits of MAC and MAC-like channels were observed in infarcted myocardium.
- CD59 and C8 binding protein were highly expressed in normal myocardium but diminished in lesions.
- Vitronectin and C4b binding protein were codeposited with MAC in infarcted areas.
Conclusions:
- The complement system, particularly MAC, actively contributes to tissue injury in myocardial infarction.
- Reduced CD59 expression on damaged cells facilitates complement attack.
- Vitronectin and C4b binding protein do not inhibit but rather associate with MAC, potentially aiding in the clearance of injured cardiac tissue.
Abstract:
Recent studies have suggested that the complement (C) system is involved in the development of tissue injury of myocardial infarction. As it is not known why the strictly controlled C system starts to react against autologous heart tissue, we have analyzed the expression of various membrane regulators of C (CR1, DAF, MCP, CD59, C8 binding protein) and the pattern of deposition of C components and plasma C regulators (C4b binding protein and vitronectin) in normal (n = 7) and infarcted (n = 13) human myocardium. In the infarcted myocardium deposits of the C membrane attack complex (MAC) were observed by immunofluorescence microscopy, and lesions resembling the transmembrane channels of MAC were detected by transmission electron microscopy. CD59 and C8 binding protein were strongly expressed by muscle cells of normal myocardial tissue. Little or no CR1, MCP, and DAF was observed on these cells. The assembly of MAC was accompanied by the deposition of vitronectin (S-protein) and C4b binding protein in the infarcted areas of myocardium. In accordance with our earlier results the expression of CD59 but not of C8 binding protein was clearly diminished in the lesions. The results show that C8 binding protein, vitronectin, and C4b binding protein do not prevent complement attack against the infarcted myocardium but rather become codeposited with the MAC. Ischemia-induced transformation of nonviable cells into complement activators, acquired loss of resistance to the MAC by shedding of CD59, and recruitment of multifunctional serum proteins by MAC could thus constitute a general process aimed at the clearance of injured tissue.