Activated Protein C Has a Protective Effect against Myocardial I/R Injury by Improvement of Endothelial Function and Activation of AKT1

OBJECTIVES Activated protein C (APC) has a protective efficacy against ischemia-reperfusion (I/R) injury in several organs. The objective of this study was to investigate effect of APC in myocardium with possible mechanism. METHODS We used regional and global myocardial I/R injury models of rats. They consisted of I/R injuries (1) by ligation of left coronary artery, or (2) using Langendorff apparatus. Langendorff was used to focus the mechanism of APC excluding coagulation cascade in a working heart. Each experiment had an APC group (n=10) and a control group with normal saline (n=10). Injections of these solutions into rats were performed 30 minutes before the planned-I/R injury. Cardiac performance after the procedure was evaluated by echocardiography or indices with Langendorff apparatus. Coronary flow (CF) was measured in the global I/R injury model. Western blotting was performed to detect the change of AKT1 signal in myocardium after global I/R injury. RESULTS LV FUNCTION IMPROVED SIGNIFICANTLY IN THE APC GROUP: %EF at 2 weeks after procedure, 70.8%± 4.5% vs. 56.5%± 0.7%; APC vs. control; p<0.01. Percent LV development pressure (LVDP) also improved in the APC group significantly, 88.8%± 45.3% vs. 28.1%± 15.4%; APC vs. control; p<0.01. In APC group, %CF improved significantly, 88.5%± 15.8% vs. 65.0%± 13.4%; APC vs. control; p<0.01. It was enhanced significantly when acetylcholine was administered; % CF: 103.5%± 9.9% vs. 87.0%± 12.1%; APC vs. control; p<0.05. Western blotting revealed that APC significantly induced activation of phosphorylated AKT1 in myocardium (p<0.05). CONCLUSIONS APC has a novel effect to protect myocardium and cardiac performance against I/R injury through improvement of endothelial function and activation of AKT1.