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Time course of complement activation and inhibitor expression after ischemic injury of rat myocardium
A Väkevä1, B P Morgan, I Tikkanen
1Department of Bacteriology and Immunology, University of Helsinki, Finland.
Insights
Complement system activation occurs rapidly in acute myocardial infarction (AMI), with early C3 deposition within 2 hours. Loss of the protective CD59 antigen coincides with membrane attack complex formation, suggesting a role in post-injury tissue clearance.
Area of Science:
- Immunology
- Cardiovascular Research
- Pathophysiology
Background:
- Complement (C) system activation is observed in myocardial infarction (MI), but its precise timing and mechanisms are unclear.
- Previous human studies linked membrane attack complex (MAC) formation to CD59 (protectin) loss in infarcted areas.
- The availability of a rat CD59 analogue enabled experimental investigation of C activation and CD59 dynamics in acute myocardial infarction (AMI).
Purpose of the Study:
- To experimentally evaluate the temporal and spatial relationship between complement component deposition and CD59 loss in acute myocardial infarction (AMI).
- To elucidate the early mechanisms of complement activation following myocardial ischemia in vivo.
Main Methods:
- Induction of AMI in rats by ligating the left coronary artery.
- Assessment of complement component deposition (C1, C3, C8, C9) and MAC formation over time.
- Evaluation of CD59 expression and localization in normal and infarcted cardiac tissue using Western blot and immunohistochemistry.
Main Results:
- Earliest sign of C activation, focal C3 deposition, observed at 2 hours post-ischemia.
- Deposition of early (C1, C3) and late (C8, C9) complement components occurred by 3 hours in AMI lesions.
- Loss of sarcolemmal CD59 in AMI lesions correlated with MAC deposits from day one; CD59 was present in normal cardiomyocytes.
Conclusions:
- Complement activation universally accompanies AMI in vivo, initiated within 2 hours by C3 deposition, potentially via the alternative pathway.
- Complement component deposition, including late pathway components, begins early (2-4 hours) after ischemia.
- Subsequent loss of protective CD59 may facilitate post-injury clearance of irreversibly damaged myocardial tissue.
Abstract:
Activation of the complement (C) system has been documented in both experimental and clinical studies of myocardial infarction, but the exact time course and mechanisms leading to C activation have remained unclear. Our earlier postmortem study on human beings showed that formation of the membrane attack complex (MAC) of C was associated with loss of CD59 (protectin), an important sarcolemmal regulator of MAC, from the infarcted area. The recent discovery of a rat analogue of CD59 has now allowed the first experimental evaluation of the temporal and spatial relationship between C component deposition and loss of CD59 in acute myocardial infarction (AMI). After ligating the left coronary artery in rats the earliest sign of C activation, focal deposition of C3, was observed at 2 hours. Deposition of the early (C1, C3) and late pathway (C8, C9) components in the AMI lesions occurred at 3 hours. Glycophosphoinositol-anchored rat CD59 was expressed in the sarcolemmal membranes of normal cardiomyocytes. In Western blot analysis extracts of normal rat heart CD59 appeared as a band of 21 kd of molecular weight under nonreducing conditions. Loss of CD59 in the AMI lesions was observed in association with deposits of MAC from day one onward. Our results show that C activation universally accompanies AMI in vivo. It is initiated within 2 hours after coronary artery obstruction via deposition of C3, which may be due to generation of the alternative pathway C3 convertase in the ischemic area. Deposition of C1 and late C components also starts during the early hours (2 to 4 hours) after ischemia. Subsequent loss of the protective CD59 antigen may initiate postinjury clearance of the irreversibly damaged tissue.