Proteasome inhibition attenuates infarct size and preserves cardiac function in a murine model of myocardial ischemia-reperfusion injury.
BACKGROUND
Despite improvements in protection, myocardial ischemia-reperfusion remains an important cause of cardiac dysfunction. Multiple strategies exist experimentally; few are clinically accessible. Nuclear factor kappa-B (NF-kappaB) is a transcription factor central to the inflammatory response and is implicated in reperfusion injury. Its activation relies on the degradation of its inhibitory molecule, IkappaB, by the 20S proteasome. We hypothesized that proteasome inhibition would decrease the extent of infarction after temporary coronary occlusion.


METHODS
C57Bl6 mice received a specific proteasome inhibitor (PS-519) and were subjected to 30 minutes of transient occlusion of the left anterior descending artery. After 24 hours of reperfusion, echocardiography was performed to evaluate ventricular function and hearts were excised and analyzed for infarct size, areas at risk, and molecular markers of injury and NF-kappaB activation.


RESULTS
Compared with controls, PS-519 delivered before left anterior descending (coronary artery) ligation reduced the area of infarct without a change in the area at risk. Similar results were seen with PS-519 delivered at reperfusion. Echocardiography demonstrated a relative reduction in fractional shortening in the vehicle group of 9.8% versus only 2.7% in the PS-519 group. Markers of myocardial stress and injury were accordingly suppressed with PS-519. These physiologic findings were associated with PS-519 decreasing p65 and TNF expression while preserving IkappaB alpha expression.


CONCLUSIONS
In this murine infarct model PS-519 significantly preserved regional myocardial function, reduced the size of infarction, and attenuated expression of myocardial inflammatory response genes. These data demonstrate that a currently available and well-tolerated inhibitor of NF-kappaB can decrease the risk of myocardial injury associated with ischemia-reperfusion.
Stansfield
William E
WE
Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7065, USA.
Moss
Nancy C
NC
Willis
Monte S
MS
Tang
Ruhang
R
Selzman
Craig H
CH
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D061988:Proteasome Inhibitors
D016328:NF-kappa B; C411422:PS519; D061988:Proteasome Inhibitors; D000111:Acetylcysteine