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Blocking of classical complement pathway inhibits endothelial adhesion molecule expression and preserves ischemic
1II. Department of Medicine, Johannes Gutenberg University, Mainz, Germany.
Insights
Exogenous C1 esterase inhibitor (C1 INH) protects against myocardial ischemia-reperfusion injury by blocking complement activation and reducing inflammatory cell adhesion. This treatment significantly reduces cardiac damage and neutrophil infiltration in rat models.
Area of Science:
- Cardiovascular Science
- Immunology
- Pharmacology
Background:
- Myocardial ischemia-reperfusion (I+R) injury involves leukocyte activation, cytokine release, and complement system activation.
- These processes contribute to significant cardiac damage following reduced blood flow and subsequent re-perfusion.
Purpose of the Study:
- To investigate the cardioprotective effects of exogenous C1 esterase inhibitor (C1 INH) in a rat model of myocardial I+R.
- To elucidate the mechanisms underlying C1 INH's potential protective role.
Main Methods:
- A rat model of myocardial I+R (20 min ischemia, 24 or 48 hr reperfusion) was utilized.
- C1 INH was administered intravenously prior to reperfusion.
- Myocardial injury was assessed by histology and myeloperoxidase (MPO) activity.
- Immunohistochemistry was used to evaluate complement C1q deposition and adhesion molecule expression (P-selectin, ICAM-1).
Main Results:
- C1 INH administration significantly attenuated myocardial injury and reduced MPO activity (a marker of neutrophil infiltration) after 24 hr of reperfusion.
- Significant cardioprotection and reduced neutrophil infiltration were also observed after 48 hr of reperfusion with C1 INH.
- C1 INH treatment abolished the deposition of C1q and the expression of P-selectin and ICAM-1 on cardiac vasculature.
Conclusions:
- Exogenous C1 INH demonstrates significant cardioprotective effects against myocardial I+R injury.
- The protective mechanisms involve blocking the classical complement pathway and reducing the expression of endothelial adhesion molecules.
- This leads to decreased polymorphonuclear leukocyte (PMN) interaction with the endothelium and diminished cardiac necrosis.
Abstract:
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 means 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.