Shen You-Tang, Depre Christophe, Yan Lin, Park Ji Yeon, Tian Bin, Jain Komal, Chen Li, Zhang Yan, Kudej Raymond K, Zhao Xin, Sadoshima Junichi, Vatner Dorothy E, Vatner Stephen F
Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ, USA.
Circulation. 2008 Nov 4;118(19):1961-9. doi: 10.1161/CIRCULATIONAHA.108.788240. Epub 2008 Oct 20.
The hypothesis of the present study was that molecular mechanisms differ markedly when mediating ischemic preconditioning induced by repetitive episodes of ischemia versus classic first- or second-window preconditioning.
To test this, chronically instrumented conscious pigs were subjected to either repetitive coronary stenosis (RCS) or a traditional protocol of second-window ischemic preconditioning (SWIPC). Lethal ischemia, induced by 60 minutes of coronary artery occlusion followed by reperfusion, resulted in an infarct size/area at risk of 6+/-3% after RCS and 16+/-3% after SWIPC (both groups P<0.05, less than shams 42+/-4%). Two molecular signatures of SWIPC, the increased expression of the inducible isoform of nitric oxide synthase and the translocation of protein kinase Cepsilon to the plasma membrane, were observed with SWIPC but not with RCS. Confirming this, pretreatment with a nitric oxide synthase inhibitor prevented the protection conferred by SWIPC but not by RCS. Microarray analysis revealed a qualitatively different genomic profile of cardioprotection between ischemic preconditioning induced by RCS and that induced by SWIPC. The number of genes significantly regulated was greater in RCS (5739) than in SWIPC (2394) animals. Of the 5739 genes regulated in RCS, only 31% were also regulated in SWIPC. Broad categories of genes induced by RCS but not SWIPC included those involved in autophagy, endoplasmic reticulum stress, and mitochondrial oxidative metabolism. The upregulation of these pathways was confirmed by Western blotting.
RCS induces cardioprotection against lethal myocardial ischemia that is at least as powerful as traditional ischemic preconditioning but is mediated through radically different mechanisms.
本研究的假设是，在介导由反复缺血发作诱导的缺血预处理与经典的第一或第二窗预处理时，分子机制存在显著差异。
为验证这一点，对长期植入仪器的清醒猪进行反复冠状动脉狭窄（RCS）或传统的第二窗缺血预处理（SWIPC）方案。由60分钟冠状动脉闭塞后再灌注诱导的致死性缺血，导致RCS后梗死面积/危险面积为6±3%，SWIPC后为16±3%（两组P<0.05，均小于假手术组的42±4%）。SWIPC的两个分子特征，即诱导型一氧化氮合酶表达增加和蛋白激酶Cε易位至质膜，在SWIPC中观察到，但在RCS中未观察到。证实这一点的是，用一氧化氮合酶抑制剂预处理可阻止SWIPC赋予的保护作用，但不能阻止RCS的保护作用。微阵列分析显示，RCS诱导的缺血预处理与SWIPC诱导的缺血预处理之间，心脏保护的基因组特征在质量上有所不同。RCS中显著调控的基因数量（5739个）多于SWIPC（2394个）动物。在RCS中调控的5739个基因中，只有31%在SWIPC中也被调控。RCS诱导但SWIPC未诱导的广泛基因类别包括参与自噬、内质网应激和线粒体氧化代谢的基因。这些途径的上调通过蛋白质印迹法得到证实。
RCS诱导对致死性心肌缺血的心脏保护作用，其作用至少与传统缺血预处理一样强大，但通过截然不同的机制介导。
