Question: 

Myocardial ischemia-reperfusion induces an inflammatory reaction in the affected area. Nuclear factor-kB (NF-kB) and hypoxia-inducible factor (HIF) seem to play a pivotal role in this inflammatory response. The proteasome system regulates their function by degradation of the inhibitory molecule (IkB) or the degradation of HIF-1a. We hypothesized that proteasome inhibition might attenuate myocardial injury and preserve cardiac function in a murine model of myocardial hibernation.

Methods: 

A hibernation protocol was applied to C57BL/6 mice and proteasome blockade was accomplished by Velcade at the onset of the first and forth reperfusion. 24 hours after the last reperfusion, cardiovascular parameters were recorded. Hearts were excised for histological, immunochemical as well as molecular investigations.

Results: 

The series of transient cardiac occlusions led to about 10.9% loss of body weight (BW) in control animals vs. 6.2% BW loss in their Velcade treated counterparts, accompanied by a reduced rate of mortality. Velcade treatment also reduced the size of ischemia induced fibrosis by about 50%. The expression of HIF-1 and -2 was significantly higher in the Velcade group. In addition, immunochemical analysis showed an increase of macrophage recruitment and vascular growth induced by the proteasome inhibitor. Recording of hemodynamic parameters revealed that transient occlusion did not impair cardiovascular characteristics neither in the control group nor in the group treated with Velcade.

Conclusion: 

During myocardial hibernation proteasome inactivation seems to decrease NF-kB and to increase HIF and thereby act cardioprotective. The proteasome system may thus be an interesting target for pharmacological intervention during myocardial injury.