Attenuation of myocardial reperfusion injury in pigs by Mirococept, a membrane-targeted complement inhibitor derived from human CR1.
OBJECTIVE
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.
Banz
Yara
Y
University of Bern, Department of Clinical Research, Bern, Switzerland.
Hess
Otto M
OM
Robson
Simon C
SC
Csizmadia
Eva
E
Mettler
Daniel
D
Meier
Pascal
P
Haeberli
André
A
Shaw
Sidney
S
Smith
Richard A
RA
Rieben
Robert
R
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000502:physiology; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D011951:Receptors, Complement / Q000627:therapeutic use*; D013318:Stroke Volume / Q000502:physiology; D013552:Swine; D019210:Troponin I / Q000097:blood; D016277:Ventricular Function, Left / Q000502:physiology