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Vol. 286, Issue 1, 429-438, July 1998
II. Department of Medicine (M.B., J.M., H.D.) and
Department of
Cardiac-Thoracic-Surgery (D.P., M.D., H.O.), Johannes Gutenberg
University, 55101 Mainz, Germany
Myocardial injury after ischemia (I) and reperfusion (R) is related to
leukocyte activation with subsequent release of cytokines and
oxygen-derived free radicals as well as complement activation. In our
study, the cardioprotective effects of exogenous C1 esterase inhibitor
(C1 INH) were examined in a rat model of myocardial I + R
(i.e., 20 min + 24 hr or 48 hr). The C1 INH (10, 50 and 100 U/kg) administered 2 min before reperfusion significantly attenuated myocardial injury after 24 hr of R compared to vehicle treated rats (P < .001). Further, cardiac myeloperoxidase
activity (i.e., a marker of PMN [polymorphonuclear
leukocyte] accumulation) in the ischemic area was significantly
reduced after C1 INH treatment compared to vehicle treated animals
(0.81 ± 0.1, 0.34 ± 0.13, 0.13 ± 0.1 vs. 1.44 ± 0.3 U/100 mg tissue, P < .001).
In addition, C1 INH (100 U/kg) significantly attenuated myocardial
injury and neutrophil infiltration even after 48 hr of reperfusion
compared to vehicle treatment. Immunohistochemical analysis of
ischemic-reperfused myocardial tissue demonstrated activation of
classical complement pathway by deposition of C1q on cardiac myocytes
and cardiac vessels. In addition, expression of the endothelial
adhesion molecules P-selectin and intercellular adhesion molecule 1 (ICAM-1) was observed after reperfusion of the ischemic myocardium. In
this regard, C1 INH administration abolished expression of P-selectin and ICAM-1 on the cardiac vasculature after myocardial ischemia and
reperfusion. Blocking the classical complement pathway by exogenous C1
INH appears to be an effective mean to preserve ischemic myocardium
from injury after 24 and 48 hr of reperfusion. The mechanisms of this
cardioprotective effect appears to be due to blocking of complement
activation and reduced endothelial adhesion molecule expression with
subsequent reduced PMN-endothelium interaction, resulting in diminished
cardiac necrosis.
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