Stansfield William E, Moss Nancy C, Willis Monte S, Tang Ruhang, Selzman Craig H
Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7065, USA.
Ann Thorac Surg. 2007 Jul;84(1):120-5. doi: 10.1016/j.athoracsur.2007.02.049.
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.
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.
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.
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.
尽管在心肌保护方面有所改善，但心肌缺血再灌注仍是心脏功能障碍的重要原因。实验中有多种策略；但临床上可用的却很少。核因子κB（NF-κB）是炎症反应的核心转录因子，与再灌注损伤有关。其激活依赖于20S蛋白酶体对其抑制分子IkappaB的降解。我们假设蛋白酶体抑制可减少短暂冠状动脉闭塞后的梗死范围。
C57Bl6小鼠接受特定的蛋白酶体抑制剂（PS-519），并对其左前降支动脉进行30分钟的短暂闭塞。再灌注24小时后，进行超声心动图检查以评估心室功能，并切除心脏，分析梗死面积、危险区域以及损伤和NF-κB激活的分子标志物。
与对照组相比，在左前降支（冠状动脉）结扎前给予PS-519可减少梗死面积，而危险区域面积无变化。在再灌注时给予PS-519也观察到类似结果。超声心动图显示，载体组的缩短分数相对降低了9.8%，而PS-519组仅为2.7%。PS-519相应地抑制了心肌应激和损伤标志物。这些生理结果与PS-519降低p65和TNF表达同时保留IkappaBα表达有关。
在这个小鼠梗死模型中，PS-519显著保留了局部心肌功能，减小了梗死面积，并减弱了心肌炎症反应基因的表达。这些数据表明，一种目前可用且耐受性良好的NF-κB抑制剂可降低与缺血再灌注相关的心肌损伤风险。
