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Cardiovascular Research 2007 76(3):482-493; doi:10.1016/j.cardiores.2007.07.016
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Copyright © 2007, European Society of Cardiology

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

Yara Banza,c, Otto M. Hessb, Simon C. Robsonc, Eva Csizmadiac, Daniel Mettlera, Pascal Meierb, André Haeberlia, Sidney Shawa, Richard A. Smithd and Robert Riebena,*

aUniversity of Bern, Department of Clinical Research, Switzerland
bCardiology, Swiss Cardiovascular Center, University Hospital, Bern, Switzerland
cHarvard University, Beth Israel Deaconess Medical Center, Boston, MA, USA
dInflazyme Pharmaceuticals Ltd., Richmond, BC, Canada

*Corresponding author. Department of Clinical Research University of Bern Murtenstrasse 31, P.O. Box 33 CH-3010 Bern, Switzerland. Tel.: +41 31 632 9669; fax: +41 31 632 8837. robert.rieben{at}dkf.unibe.ch

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.

KEYWORDS Ischemia; Reperfusion; Complement; Complement receptor 1; Endothelium; Mirococept

Abbreviations: AAR, area at risk • ANR, area not at risk • aPTT, activated partial thromboplastin time • CH50, (classical pathway) complement activity • CR1, complement receptor 1 • EC, endothelial cell • EF, ejection fraction • ELISA, enzyme-linked immunosorbent assay • ET-1, endothelin-1 • FS, fractional shortening • HR, heart rate • I/R, ischemia/reperfusion • LAD, left anterior descending artery • LVEDP, left ventricular end-diastolic pressure • LVM, left ventricular mass • MAP, mean arterial pressure • MI, myocardial infarction • MPO, myeloperoxidase • NIT, necrotic ischemic tissue • TF, tissue factor • TTC, triphenyl tetrazolium chloride • TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling • VIT, vital ischemic tissue


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