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Attenuation of myocardial reperfusion injury in pigs by Mirococept, a membrane-targeted complement inhibitor derived from human CR1

Banz, Yara ; Hess, Otto M. ; Robson, Simon C. ; Csizmadia, Eva ; Mettler, Daniel ; Meier, Pascal ; Haeberli, André ; Shaw, Sidney ; Smith, Richard A. ; Rieben, Robert

In: Cardiovascular Research, 2007, vol. 76, no. 3, p. 482-493

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    Titre
    • Attenuation of myocardial reperfusion injury in pigs by Mirococept, a membrane-targeted complement inhibitor derived from human CR1
    Auteur
    • Banz, Yara. University of Bern, Department of Clinical Research, Switzerland
    • Hess, Otto M.. Cardiology, Swiss Cardiovascular Center, University Hospital, Bern, Switzerland
    • Robson, Simon C.. Harvard University, Beth Israel Deaconess Medical Center, Boston, MA, USA
    • Csizmadia, Eva. Harvard University, Beth Israel Deaconess Medical Center, Boston, MA, USA
    • Mettler, Daniel. University of Bern, Department of Clinical Research, Switzerland
    • Meier, Pascal. Cardiology, Swiss Cardiovascular Center, University Hospital, Bern, Switzerland
    • Haeberli, André. University of Bern, Department of Clinical Research, Switzerland
    • Shaw, Sidney. University of Bern, Department of Clinical Research, Switzerland
    • Smith, Richard A.. Inflazyme Pharmaceuticals Ltd., Richmond, BC, Canada
    • Rieben, Robert. University of Bern, Department of Clinical Research, Switzerland
    Type de document
    • Postprint
    Identifiant OAI-PMH
    • oai:doc.rero.ch:297174
    Summary
    Objectives Membrane-targeted application of complement inhibitors may ameliorate ischemia/reperfusion (I/R) injury by directly targeting damaged cells. We investigated whether Mirococept, a membrane-targeted, myristoylated peptidyl construct derived from complement receptor 1 (CR1) could attenuate I/R injury following acute myocardial infarction in pigs. Methods In a closed-chest pig model of acute myocardial infarction, Mirococept, the non-tailed derivative APT154, or vehicle was administered intracoronarily into the area at risk 5 min pre-reperfusion. Infarct size, cardiac function and inflammatory status were evaluated. Results Mirococept targeted damaged vasculature and myocardium, significantly decreasing infarct size compared to vehicle, whereas APT154 had no effect. Cardioprotection correlated with reduced serum troponin I and was paralleled by attenuated local myocardial complement deposition and tissue factor expression. Myocardial apoptosis (TUNEL-positivity) was also reduced with the use of Mirococept. Local modulation of the pro-inflammatory and pro-coagulant phenotype translated to improved left ventricular end-diastolic pressure, ejection fraction and regional wall motion post-reperfusion. Conclusions Local modification of a pro-inflammatory and pro-coagulant environment after regional I/R injury by site-specific application of a membrane-targeted complement regulatory protein may offer novel possibilities and insights into potential treatment strategies of reperfusion-induced injury