Introduction: Alpha-2 macroglobulin (A2M) is a protein abundant in plasma known for its anti-inflammatory properties. A2M is cleared from the circulation by binding a membrane receptor, low-density lipoprotein related protein 1 (LRP1). Recent studies have shown that LRP1 functions not only as a scavenger receptor but also transduces a cell survival signal.
Hypothesis: Administration of A2M at time of reperfusion in an experimental model of myocardial ischemia-reperfusion may reduce the infarct size by reducing the injury following reperfusion.
Methods: We used adult male CD1 mice for the experiments. Cardiac function was measured non-invasively with transthoracic echocardiography. We induced myocardial ischemia by temporary ligation of the left coronary artery for 30 minutes followed by reperfusion for 24 hours. Infarct size was measured at pathology using the triphenyl-tetrazolium-chloride staining for viable myocardium and phtalo blue perfusion for non-risk myocardium, and expressed as percent of myocardium at risk. We administered A2M at 3, 10, 30 or 60 mg/kg or a matching volume of NaCl 0.9% solution (vehicle) as a single dose at time of reperfusion.
Results: Administration of A2M at any dose provided a significant reduction infarct size compared with vehicle (Figure). The dose-response curve showed a U-shaped response with a greater response for the intermediate doses of 10 and 30 mg/kg (Figure).
Conclusion: Plasma derived A2M, an anti-inflammatory protein known to bind membrane LRP1, provides a cardioprotective signal across a large dose range. Additional studies are required to better characterized the U-shaped response and explore the potential translational value of this treatment.