Ischemic but Not Pharmacological Preconditioning Requires Protein Synthesis

Abstract

Background —Ischemic preconditioning (IPC) and pharmacological preconditioning (PPC) have both been shown to confer cardioprotective effects. However, the role of protein synthesis in preconditioning is unclear. Methods and Results —Isolated rabbit hearts were treated with cycloheximide (CHx, 10 μmol/L), a protein synthesis inhibitor at the translational level, before 2 cycles of IPC (5 minutes of global ischemia/5 minutes of reperfusion, n=6) or PPC by pinacidil (PIN, 10 μmol/L; n=6), an ATP-sensitive potassium channel opener. Six rabbit hearts received actinomycin D (Act D, 20 μmol/L; n=6), a protein synthesis inhibitor at the transcriptional level, before IPC. The left anterior descending coronary artery was then occluded for 60 minutes and reperfused for 120 minutes. Control hearts received no treatment before prolonged ischemia (n=6). Left ventricular pressure, action potential duration, and coronary flow were measured. Infarct size is expressed as a percentage of the area at risk. IPC (n=6) and PIN (n=8) hearts experienced reduced infarct size compared with control hearts (22±3% and 27±2% versus 46±3%, IPC and PIN versus control; P <0.01). Translational blockade (CHx) reversed the IPC infarct size reduction effect (22±3% versus 48±4%, IPC versus CHx+IPC; P <0.01) but not the effects of pinacidil (27±2% versus 29±3%, PIN versus CHx+PIN; P =NS). Transcriptional blockade (Act D) did not abolish the IPC effect (23±5% versus 22±3%, Act D+IPC versus IPC; P =NS). There were no significant differences in electromechanical function consequent to CHx and Act D treatment. Conclusions —These findings suggest an important role for protein synthesis in the mechanism for IPC-mediated protection at the translational level, which may be different from PPC.