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Loss of expression of protectin (CD59) is associated with complement membrane attack complex deposition in myocardial
1Department of Bacteriology and Immunology, University of Helsinki, Finland.
Insights
Protectin (CD59), a complement inhibitor, is found in healthy heart muscle but is lost in myocardial infarction. This loss correlates with complement system attack, suggesting a role in heart attack development.
Area of Science:
- Cardiovascular Biology
- Immunology
- Complement System
Background:
- Protectin (CD59) is a known inhibitor of the complement membrane attack complex (MAC).
- Its role in cardiac tissue and relation to myocardial infarction (MI) was previously unclear.
Purpose of the Study:
- Investigate protectin expression in human heart tissue.
- Examine the relationship between MAC deposition and protectin levels in MI.
Main Methods:
- Analyzed myocardial tissue from MI patients and controls using immunofluorescence.
- Purified and characterized myocardial protectin.
- Assessed protectin's membrane anchorage and its presence in infarcted areas.
Main Results:
- Protectin (CD59) is expressed in sarcolemmal membranes of normal myocardium.
- Purified heart protectin matched urinary CD59 in molecular weight and sequence.
- CD59 expression was lost or reduced in MI lesions (1-14 days old), coinciding with MAC deposition.
- CD59 shedding via vesicles was observed in border zones.
Conclusions:
- Glycophosphoinositol-anchored CD59 is present in healthy heart sarcolemma but absent in infarcted myocardium.
- Acquired loss of CD59 may lead to complement-mediated damage, contributing to MI pathophysiology.
Background:
Protectin (CD59) is a recently discovered inhibitor of the complement membrane attack complex (MAC). In the present study we investigated expression of protectin in human heart and examined the relationship between MAC deposition and protectin in myocardial infarction.
Experimental Design:
Myocardial tissue specimens were obtained at autopsy from patients who had died of myocardial infarction (n = 10) or other causes (n = 5). MAC and protectin were detected by indirect immunofluorescence microscopy analysis in the heart sections by using antibodies against individual components of MAC, MAC neoantigens and protectin. Myocardial protectin was purified by affinity chromatography and compared with the previously characterized erythrocyte and urinary protectins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis, N-terminal amino acid sequencing, and testing its ability to bind to the terminal complement complex. The possible glycophosphoinositol-type anchorage of protectin in the heart was examined by treating myocardial sections with glycophosphoinositol-specific phospholipase C.
Results:
Immunoblotting and immunofluorescence analysis showed expression of protectin in the sarcolemmal membranes of normal myocardium. Protectin purified from normal human heart tissue had the same molecular weight and N-terminal amino acid sequence as CD59 purified from urine. In sucrose density ultracentrifugation analysis it was observed to bind efficiently to the SC5b-8 complex. In normal myocardium the expression of CD59 was sensitive to treatment with glycophosphoinositol-specific phospholipase C. The expression of CD59 was lost or clearly diminished in infarcted lesions aged 1-14 days. Loss of CD59 expression was accompanied by concomitant deposition of the MAC within the CD59-negative lesions. In border areas between an infarcted lesion and normal tissue, CD59 often appeared in small vesicles, suggesting shedding as a possible mechanism for its removal.
Conclusions:
Glycophosphoinositol-anchored CD59 is expressed in the sarcolemmal membranes of normal heart but lost from infarcted myocardium. Acquired loss of resistance to autologous complement and subsequent complement attack may thus be involved in the pathophysiology of myocardial infarction.