Objective: Myocardial ischemia-reperfusion is still an important cause of cardiac dysfunction. Nuclear factor-kB (NF-kB) and hypoxia-inducible factor-1a (HIF- 1a) seem to play a privotal role in the inflammatory response and are implicated in myocardial infarction. The proteasome system regulates their function by degradation of the inhibitory molecule (IkB) or the degradation of HIF-1a. We hypothesized that proteasome inhibition would attenuate infarct size and preserve cardiac function in a murine model of myocardial hibernation. Methods: For 7 days C57BL/6 mice were subjected daily to 15 minutes of transient occlusion of the left anterior descending artery. A proteasome blockade by Velcade® was initiated at the onset of the first and forth reperfusion. The control group received an equivalent dose of NaCl 0.9%. 24 hours after the last reperfusion, hemodynamic measurements were performed by Millar catheter recordings of peripheral and intraventricular pressure to evaluate cardiovascular function. Hearts were excised and histological sections were prepared for the calculation of infarct size. Additional hearts were preserved for analysis of molecular markers of inflammation and injury, as well as NF-kB activation. Results: Hemodynamic data demonstrated that transient occlusion did not influence peripheral and intraventricular blood pressures neither in the control group nor in the group treated with Velcade. Compared to controls, Velcade reduced the size of infarction significantly by about 50% and diminished mortality by 59%. Conclusion: During myocardial hibernation proteasome activation seems to increase mortality and to enlarge infarct size. As its inhibition by Velcade improved survival and decreased cardiac injury possibly by reduction of NF-kB and/or HIF-1a activation. The proteasome system may thus be an interesting target for pharmacological intervention during myocardial injury.