Fenton Richard A, Dickson Eric W, Dobson James G
Department of Physiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.
Life Sci. 2005 Nov 12;77(26):3375-88. doi: 10.1016/j.lfs.2005.05.047. Epub 2005 Aug 15.
Brief, nonlethal episodes of ischemia in the mammalian heart provide cardioprotection against the detrimental effects of a longer duration ischemia. The manifestation of this preconditioning (PC) phenomenon is initiated by the enhanced phosphorylation state of signal transduction proteins. We reported previously that PC is decreased in the aged rat myocardium. Although the mechanism responsible for this loss is not understood, a reduction in the phosphorylation of critical proteins associated with PC may be postulated. Experiments were conducted to investigate whether PC in the aged heart can be restored with the inhibition of endogenous protein phosphatases thereby enhancing phosphorylation of signaling proteins. Levels of phosphatase activities were also assessed with adult heart aging. Hearts from young adult (3-4 mo.) and aged (21-22 mo.) Fischer-344 rats were perfused in the presence or absence of okadaic acid (OKA; 0.1 microM). Aged adult hearts were either not preconditioned or were preconditioned with two PC cycles (5 min ischemia/5 min reperfusion). Myocardial cellular death that developed with a subsequent ischemia was determined with triphenyltetrazolium. With PC, 55% of the aged heart after ischemia was no longer viable. OKA administered before or after ischemia reduced this ischemia-induced cellular death by 29%. Without PC, OKA reduced viability 18% only when present before and after the ischemic episode. OKA in the ischemic young heart during reperfusion reduced the loss of viability 31%. The Protein Phosphatase 2A (PP2A) activity was found to be up to 82% greater in ventricular myocardium of aged rats. In conclusion, aging-induced changes in protein dephosphorylation may be one mechanism reducing the manifestation of preconditioning in the aged heart.
哺乳动物心脏短暂的、非致死性缺血发作可提供心脏保护，抵御更长时间缺血的有害影响。这种预处理（PC）现象的表现是由信号转导蛋白增强的磷酸化状态引发的。我们之前报道过，老年大鼠心肌中的PC降低。尽管导致这种丧失的机制尚不清楚，但可以推测与PC相关的关键蛋白磷酸化减少。进行实验以研究老年心脏中的PC是否可以通过抑制内源性蛋白磷酸酶来恢复，从而增强信号蛋白的磷酸化。还评估了成年心脏衰老过程中的磷酸酶活性水平。在有或没有冈田酸（OKA；0.1微摩尔）的情况下，对年轻成年（3 - 4个月）和老年（21 - 22个月）的Fischer - 344大鼠的心脏进行灌注。老年成年心脏要么不进行预处理，要么进行两个PC周期（5分钟缺血/5分钟再灌注）预处理。用三苯基四氮唑确定随后缺血时发生的心肌细胞死亡。经过PC处理后，缺血后55%的老年心脏不再存活。在缺血前或缺血后给予OKA可使这种缺血诱导的细胞死亡减少29%。没有进行PC处理时，仅在缺血发作前后存在OKA时，其可使存活率降低18%。再灌注期间缺血的年轻心脏中的OKA可使存活率损失降低31%。发现老年大鼠心室心肌中的蛋白磷酸酶2A（PP2A）活性比年轻大鼠高82%。总之，衰老诱导的蛋白去磷酸化变化可能是老年心脏中预处理表现降低的一种机制。
