Reduction of Myocardial Ischemia-Reperfusion Injury by Inhibiting Interleukin-1 Alpha

Background: Interleukin-1 alpha (IL-1 alpha) released by dying cells is an alarmin that activates the innate immunity. We hypothesized that after myocardial ischemia-reperfusion (I/R) injury, IL-1 alpha amplifies the myocardial damage by activating the inflammasome and caspase-1. Methods: Adult male CD1 mice were used. The left anterior descending coronary artery was ligated for 30 minutes, after 24 hours of reperfusion. An IL-1 alpha blocking antibody (15 mu g/kg intraperitoneally) or matching vehicle was given after reperfusion. A subgroup of mice underwent sham surgery. We assessed the effects of IL-1 alpha blockade on caspase-1 activity, infarct size, cardiac troponin I serum levels, and left ventricular fractional shortening, 24 hours after I/R. Results: I/R led to inflammasome formation, and IL-1a blockade significantly reduced inflammasome formation, reflected by >50% reduction in caspase-1 activity versus vehicle (P = 0.03). IL-1 alpha blockade also reduced the infarct size (-52% infarct expressed as percentage of area at risk, and -79% for cardiac troponin I serum levels, P < 0.001 vs. vehicle) and preserved the left ventricular fractional shortening (31 +/- 3% vs. 25 +/- 2%, P < 0.001 vs. vehicle). Conclusion: IL-1 alpha blockade after I/R reduces the inflammasome activation, decreases the infarct size, and preserves the left ventricular function. IL-1 alpha blockade may therefore represent a novel therapeutic strategy to reduce I/R injury.