Liu Peitan, Xu Baohuan, Cavalieri Thomas A, Hock Carl E
Department of Cell Biology and New Jersey Institute of Successful Aging, University of Medicine and Dentistry of New Jersey, School of Osteopathic Medicine, Stratford, New Jersey, USA.
Shock. 2008 Nov;30(5):545-51. doi: 10.1097/SHK.0b013e31816a192d.
Ischemic heart disease is a common age-related disease. Apoptotic cell death and inflammation are the major contributors to I/R injury. The mechanisms that trigger myocyte apoptosis and inflammation during myocardial I/R (MI/R) remain to be elucidated. Published data from our laboratory demonstrated that pretreatment of MI/R rats with pifithrin-alpha (PFT), a specific p53 inhibitor, reduced myocyte apoptosis and improved cardiac function compared with MI/R rats pretreated with saline at 4 h of reperfusion. In the present study, we investigated the effects of PFT on the occurrence of myocyte apoptosis and leukocyte transmigration in the later period of reperfusion. Aged (20-month-old) male F344 rats were subjected to 30 min of myocardial ischemia via ligature of the LCA, followed by 24 h of reperfusion. Pifithrin-alpha (2.2 mg/kg, intraperitoneally) or saline was administered to rats before ischemia. The results indicate that pretreatment of MI/R rats with PFT significantly decreased the percentage of infarct area to ischemic area (33 +/- 8 vs. 54 +/- 9, P < 0.05) and improved cardiac output (79 +/- 11 vs. 38 +/- 9 mL/min per 100 g body weight, P < 0.05) when compared with rats pretreated with saline at 24 h of reperfusion. The protective effects of PFT may involve the p53/Bax-mediated apoptosis because treatment of MI/R rats with PFT attenuated the ratio of Bax to Bcl2 (0.97 +/- 0.1 vs. 2.1 +/- 0.2, P < 0.05) and reduced myocyte apoptosis. Interestingly, inhibition of p53 transcriptional function by PFT alleviated leukocyte infiltration into the ischemic area of the heart (339 +/- 37 vs. 498 +/- 75 cells/10 high-power fields, P < 0.05). These data suggest that inhibition of p53 transcriptional function by PFT attenuates myocyte apoptosis and alleviates leukocyte transmigration at 24 h of reperfusion. The mechanisms by which p53 modulates leukocyte transmigration require further investigation.
缺血性心脏病是一种常见的与年龄相关的疾病。凋亡性细胞死亡和炎症是缺血/再灌注损伤的主要原因。心肌缺血/再灌注（MI/R）期间触发心肌细胞凋亡和炎症的机制仍有待阐明。我们实验室已发表的数据表明，用特异性p53抑制剂匹非尼酮-α（PFT）预处理MI/R大鼠，与在再灌注4小时时用生理盐水预处理的MI/R大鼠相比，可减少心肌细胞凋亡并改善心脏功能。在本研究中，我们调查了PFT对再灌注后期心肌细胞凋亡发生和白细胞迁移的影响。将老年（20月龄）雄性F344大鼠通过结扎左冠状动脉进行30分钟的心肌缺血，随后进行24小时的再灌注。在缺血前给大鼠腹腔注射匹非尼酮-α（2.2mg/kg）或生理盐水。结果表明，与在再灌注24小时时用生理盐水预处理的大鼠相比，用PFT预处理MI/R大鼠可显著降低梗死面积与缺血面积的百分比（33±8 vs. 54±9，P<0.05）并改善心输出量（79±11 vs. 38±9 mL/min per 100 g体重，P<0.05）。PFT的保护作用可能涉及p53/Bax介导的凋亡，因为用PFT处理MI/R大鼠可减弱Bax与Bcl2的比率（0.97±0.1 vs. 2.1±0.2，P<0.05）并减少心肌细胞凋亡。有趣的是，PFT对p53转录功能的抑制减轻了白细胞浸润到心脏缺血区域（339±37 vs. 498±75个细胞/10个高倍视野，P<0.05）。这些数据表明，PFT对p53转录功能的抑制在再灌注24小时时可减轻心肌细胞凋亡并减轻白细胞迁移。p53调节白细胞迁移的机制需要进一步研究。
