Profound cardioprotection with chloramphenicol succinate in the swine model of myocardial ischemia-reperfusion injury.
Profound cardioprotection with chloramphenicol succinate in the swine model of myocardial ischemia-reperfusion injury.
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DOI：
10.1161/circulationaha.109.928242
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发表时间：
2010-09-14
期刊：
影响因子：
37.8
通讯作者：
Przyklenk K
中科院分区：
文献类型：
--
作者：
Sala-Mercado JA;Wider J;Undyala VV;Jahania S;Yoo W;Mentzer RM Jr;Gottlieb RA;Przyklenk K
新出现的证据表明，“适应性”诱导自噬(负责蛋白质和细胞器的降解和循环的细胞过程)可能提供一种心脏保护表型，并代表一种限制缺血再灌注损伤的新策略。我们的目的是在一个临床相关的急性心肌梗死的大型动物模型中测试这一范式。麻醉猪冠状动脉结扎45min，再灌流3h。在研究的第一部分，猪在缺血前10分钟注射氯霉素琥珀酸酯(CAPS：一种据称能上调自噬的试剂；20 mg/kg)或生理盐水。用四唑盐染色显示梗死灶的大小，并以危险心肌的百分比表示。在不同的动物中，分别在基线和CAPS处理后10分钟采集心肌样本，并(通过免疫印迹)检测与自噬形成有关的两种蛋白质：Beclin-1和轻链(LC)3B-II。为了研究延迟治疗是否能维持CAPS的疗效，在阻断后30分钟给另外的猪注射CAPS(20 mg/kg)。在再灌流结束时检测Beclin-1和Lc3B-II的表达以及心肌梗死面积。CAPS具有心脏保护作用：CAPS预处理组和CAPS延迟处理组的心肌梗死面积分别为25±5%和41±4%，而生理盐水对照组为56±5%(P<；0.01和P<；0.05与对照组相比)。此外，服用CAPS与这两种蛋白的表达增加有关。我们的结果表明，CAPS可减轻缺血-再灌注损伤，并与自噬诱导可能提供一种新的心肌保护策略的概念一致。
Emerging evidence suggests that ‘adaptive’ induction of autophagy (the cellular process responsible for the degradation and recycling of proteins and organelles) may confer a cardioprotective phenotype and represent a novel strategy to limit ischemia-reperfusion injury. Our aim was to test this paradigm in a clinically relevant, large animal model of acute myocardial infarction. Anesthetized pigs underwent 45 min of coronary artery occlusion and 3 hours of reperfusion. In the first component of the study, pigs received chloramphenicol succinate (CAPS: an agent that purportedly up-regulates autophagy; 20 mg/kg) or saline at 10 min before ischemia. Infarct size was delineated by tetrazolium staining and expressed as a % of the at-risk myocardium. In separate animals, myocardial samples were harvested at baseline and 10 min following CAPS treatment and assayed (by immunoblotting) for two proteins involved in autophagomsome formation: Beclin-1 and light chain (LC) 3B-II. To investigate whether the efficacy of CAPS was maintained with ‘delayed’ treatment, additional pigs received CAPS (20 mg/kg) at 30 min post-occlusion. Expression of Beclin-1 and LC3B-II, as well as infarct size, were assessed at end-reperfusion. CAPS was cardioprotective: infarct size was 25±5% and 41±4% in the CAPS-pretreated and CAPS-delayed treatment groups versus 56±5% in saline-controls (p<0.01 and p<0.05 versus control). Moreover, administration of CAPS was associated with increased expression of both proteins. Our results demonstrate attenuation of ischemia-reperfusion injury with CAPS, and are consistent with the concept that induction of autophagy may provide a novel strategy to confer cardioprotection.