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Published on: May 6, 2018
Anti-inflammatory actions of aprotinin provide dose-dependent cardioprotection from reperfusion injury
Jm Carter1, U Buerke, E Rössner
1Department of Medicine III, Martin-Luther-University, Halle, Germany.
Background And Purpose:
Myocardial injury following ischaemia and reperfusion has been attributed to activation and transmigration of polymorphonuclear leukocytes (PMNs) with release of mediators including oxygen-derived radicals and proteases causing damage.
Experimental Approach:
We studied the serine protease inhibitor aprotinin in an in vivo rabbit model of 1 h of myocardial ischaemia followed by 3 h of reperfusion (MI+R). Aprotinin (10,000 Ukg(-1)) or its vehicle were injected 5 min prior to the start of reperfusion.
Key Results:
Myocardial injury was significantly reduced with aprotinin treatment as indicated by a reduced necrotic area (11+/-2.7% necrosis as percentage of area at risk after aprotinin; 24+/-3.1% after vehicle; P<0.05) and plasma creatine kinase activity (12.2+/-1.5 and 17.3+/-2.3 IU g(-1) protein in aprotinin and vehicle groups, respectively, P<0.05). PMN infiltration (assessed by myeloperoxidase activity) was significantly decreased in aprotinin-treated animals compared to vehicle (P<0.01). Histological analysis also revealed a substantial increase in PMN infiltration following MI+R and this was significantly reduced by aprotinin therapy (44+/-15 vs 102+/-2 PMN mm2 in aprotinin vs vehicle-treated animals, P<0.05). In parallel in vitro experiments, aprotinin inhibited neutrophil-endothelium interaction by reducing PMN adhesion on isolated, activated aortic endothelium. Finally, immunohistochemical analysis illustrated aprotinin significantly reduced myocardial apoptosis following MI+R.
Conclusions And Implications:
Inhibition of serine proteases by aprotinin inhibits an inflammatory cascade initiated by MI+R. The cardioprotective effect appears to be at least partly due to reduced PMN adhesion and infiltration with subsequently reduced myocardial necrosis and apoptosis.
Insights
Aprotinin, a serine protease inhibitor, significantly reduces myocardial injury after ischemia and reperfusion by inhibiting polymorphonuclear leukocyte infiltration. This cardioprotective effect lessens cardiac necrosis and apoptosis.
Area of Science:
- Cardiovascular Research
- Inflammation and Immunology
- Pharmacology
Background:
- Myocardial ischemia-reperfusion (MI+R) injury involves polymorphonuclear leukocyte (PMN) activation and mediator release.
- Serine proteases contribute to the inflammatory cascade and subsequent myocardial damage.
Purpose of the Study:
- To investigate the cardioprotective effects of the serine protease inhibitor aprotinin in a rabbit model of MI+R.
- To determine if aprotinin reduces PMN infiltration and myocardial apoptosis.
Main Methods:
- A rabbit model of 1-hour ischemia followed by 3-hour reperfusion was used.
- Aprotinin was administered intravenously prior to reperfusion.
- Myocardial necrosis, creatine kinase activity, PMN infiltration (myeloperoxidase activity), and apoptosis were assessed.
Main Results:
- Aprotinin significantly reduced the necrotic area and plasma creatine kinase activity.
- PMN infiltration into the myocardium was significantly decreased by aprotinin treatment.
- Aprotinin inhibited neutrophil-endothelium interaction in vitro and reduced myocardial apoptosis in vivo.
Conclusions:
- Aprotinin exerts cardioprotection by inhibiting the inflammatory cascade initiated by MI+R.
- Reduced PMN adhesion and infiltration contribute to the beneficial effects of aprotinin.
- Aprotinin effectively mitigates myocardial necrosis and apoptosis following ischemia-reperfusion.
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