p38参与单磷酰脂A预处理的延迟保护作用

Participation of p38 in late phase of cardioprotection preconditioned by monophosphoryl lipid A

目的探讨丝裂素活化蛋白激酶p38MAPK是否参与单磷酰脂A(MLA)预处理的延迟保护作用。方法建立大鼠心肌缺血/再灌注损伤(I/R)模型。分别应用MLA、p38的特异性抑制剂SB203580预处理心脏,24h后对心脏进行缺血再灌注,观察各组心功能、心肌梗死范围、血浆乳酸脱氢酶(LDH)活性,同时用Western印迹法检测MLA预处理后即刻、10、15、30min、SB203580加单磷酰脂A预处理15min时p38磷酸化水平。结果MLA预处理组较I/R组心功能明显改善,心梗范围明显缩小,血浆LDH活性升高程度减轻(P<0.01)。p38磷酸化在MLA预处理后即刻稍微增高,10min轻度升高、15min达到高峰、30min开始下降,而用SB203580可明显抑制p38活性,且预处理延迟保护作用被消除,分别与单纯缺血再灌注组相似(P>0.05)。结论MLA预处理对24h后缺血/再灌注心肌有保护作用。p38参与心肌预处理后的延迟保护作用,MLA预处理后p38适度激活可能是药物延迟保护作用的重要机制之一。

Objective To investigate the role of p38MAPK in the late phase of cardioprotection induced by monophosphoryl lipid A (MLA ) on ischemia/reperfusion (I/R) injury in rat's heart .Methods A ischemic-reperfusion(I/R) model of rats was established. The heart preconditioned by specific inhibitor SB203580 of MLA and p38 was conducted ischemia/reperfusion at 24 h later to observe cardiac function, myocardial infarction and plasma lactate dehydrogenase (LDH) activity in each group. While p38 phosphorylation levels at once, at 10, 15 and 30 min after preconditioning with MLA and at 15 min after preconditioning with SB203580 and MLA were determined by Western blot. Results The heart function were improved significantly, infarct size remarkably reduced, increase of LDH activity reduced in MLA group compared to those in I/R group (P<0.01). The protective effects of MLA were completely abolished by p38MAPK inhibitor SB203580.The activities of p38MAPK rapidly increased at 10 min after MLA, reached at peak at 15 min, then begun to descend at 30 min. The activities of p38 at 15 min after SB203580+MLA administration were reduced significantly and cardioprotection in the late phase was eliminated compared to those of I/R group (P>0.05).Conclusions ①MLA preconditioning could play protective role in cardiac muscle of ischemia/reperfusion. ②p38 could participate in the cardioprotection, and its activation after MLA preconditioning might be one of important mechanisms of protective role of drugs.