FR167653 diminishes infarct size in a murine model of myocardial ischemia-reperfusion injury.

P38丝裂原活化蛋白激酶（MAPK）在心肌缺血再灌注损伤中被激活。我们在局部MI/R的实验模型中检测了p38 MAPK的高度特异性抑制剂FR 167653的作用。<Method>:CD-1小鼠在左前降支动脉短暂闭塞30分钟之前24小时腹膜内接受Fr 167653，随后再灌注120分钟。用磷酸化的p38 MAPK或其底物活化转录因子-2的单克隆抗体通过Western印迹法测定P38 MAPK活化和激酶活性。通过检测核因子（NF）-κ B向细胞核的转位来测定NF-κ B活性。用核糖核酸酶保护试验检测炎性细胞因子的表达。<Results>:在MI/R之前用FR 167653预处理小鼠导致p38 MAPK磷酸化减少（p= 0.018），抑制p38 MAPK活性（p.047），NF-kB核较少（P= 0.001），并且炎症反应性表达减少，（肿瘤坏死因子-a：p= 0.023;白细胞介素01 b：p= 0.038;肌细胞趋化蛋白-1：p= 0.001）和显著较小的梗塞发展（p= 0.0069）。在MI/R后观察到c-Jun NH 2-末端激酶和细胞外信号调节激酶的活化，而不受FR 167653的抑制<Conclusion>：我们得出结论，FR 167653在局部MI/R损伤期间选择性地抑制p38 MAPK活化和活性，并有效地减小梗死面积（73.6%）。因此，p38 MAPK抑制可能在MI/R的治疗中起作用。

P38 mitogen-activated protein kinase (MAPK) is activated during myocardial ischemia-reperfusion (MI/R) injury. we examined the effect of a highly specific inhibitor of p38 MAPK, FR167653, in an experimental model of regional MI/R.<Method> : CD-1 mice received Fr167653 intraperitoneally 24 hours prior to 30 minutes of transient occlusion of the left anterior descending artery, followed by 120 minutes of reperfusion. P38 MAPK activation and kinase activity were determined by Western blotting with monoclonal antibodies for the phosphorylated from of p38 MAPK or its substrate, activating transcription factor -2. Nuclear factor (NF) -kB activity was measured by detecting translocation of NF-kB to the nucleus. The expression of inframmatory cytokines was measured by ribonuclease protection assay.<Results> : Pretreatment of mice with FR167653 before MI/R resulted in reduction in p38 MAPK phosphorylation (p=.018), inhibition of p38 MAPK activity (p.047), less nulear of NF-kB(P=.001), and a decrease in the expression of inflammatory cytokiness (tumor necrosis factor-a : p=.023, ;interleukine01b : p=.038 ; mynocyte chemotacic protein-1 : p=.001) in the heart and the development of a significantly smaller infarct(p=.0069), when comared to hearts from mice trasted with vehicle aone. Activation of c-Jun NH2-terminal kinase and extracellular signa-regulated kinase were observed after MI/R, while not inhibited by FR167653<Conclusion> : we conclude that FR167653 selectively inhibits p38 MAPK activation and activity during regional MI/R injury and efficaciously reduces infarct size (by 73.6%). Thus, p38 MAPK inhibition may have a role in the treatment of MI/R