[HTML][HTML] Role of the complement components C5 and C3a in a mouse model of myocardial ischemia and reperfusion injury

MN Busche, GL Stahl - GMS German Medical Science, 2010 - ncbi.nlm.nih.gov
MN Busche, GL Stahl
GMS German Medical Science, 2010ncbi.nlm.nih.gov
Objective: Ischemic heart disease is the leading cause of death worldwide. The complement
system plays a major role in inflammation and tissue injury following myocardial ischemia
and reperfusion (MI/R) injury. Systemic C5 inhibition in clinical studies has resulted in mixed
results and the role of earlier complement components (eg, C3a), upstream from C5
cleavage, has not been elucidated for MI/R injury. Therefore, we evaluated the role of C5 or
C3a in a mouse model of MI/R injury. Methods: We performed experimental MI/R with 30 min …
Abstract
Objective: Ischemic heart disease is the leading cause of death worldwide. The complement system plays a major role in inflammation and tissue injury following myocardial ischemia and reperfusion (MI/R) injury. Systemic C5 inhibition in clinical studies has resulted in mixed results and the role of earlier complement components (eg, C3a), upstream from C5 cleavage, has not been elucidated for MI/R injury. Therefore, we evaluated the role of C5 or C3a in a mouse model of MI/R injury.
Methods: We performed experimental MI/R with 30 min of ischemia and 4 hr of reperfusion in 8–12 wk old C57BL/6 (WT) mice. Systemic C5 or C3a inhibition was performed with an anti-C5 monoclonal antibody (BB5. 1) 30 min prior to reperfusion or with a C3a receptor antagonist (C3aRA). Since the C3aRA induces neutropenia that resolves within 120 min, we administered C3aRA at two different time points in two separate groups: 30 min prior to reperfusion within the neutropenic time frame and 120 min prior to reperfusion, when the neutropenia had resolved, but C3aRA remained active. Following MI/R, cardiac function was assessed via echocardiography, serum troponin I concentrations were measured as an index of myocardial cell death and myocardial inflammation was determined via myocardial polymorphonuclear leukocyte (PMN) infiltration.
Results: In wild type mice, MI/R significantly decrease myocardial ejection fraction and increased serum troponin I levels and myocardial PMN infiltration compared to sham-operated animals. Systemic C5 inhibition, 30 min prior to reperfusion, significantly protected mice from MI/R injury, confirming an important role for C5 in murine MI/R injury.
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