Does p53 Inhibition Suppress Myocardial Ischemia-Reperfusion Injury?
Does p53 Inhibition Suppress Myocardial Ischemia-Reperfusion Injury?
复制标题
DOI：
10.1177/1074248418763612
复制
发表时间：
2018-07
影响因子：
2.6
通讯作者：
Steenbergen C
中科院分区：
文献类型：
--
作者：
Yano T;Abe K;Tanno M;Miki T;Kuno A;Miura T;Steenbergen C
众所周知p53是细胞凋亡和自噬的调节因子。此外，最近的研究表明，p53是线粒体通透性转换孔（mPTP）开放的调节剂，这是坏死的触发事件，但p53在心肌缺血-再灌注（I/R）诱导的坏死中的作用尚不清楚。本研究的目的是确定p53在急性心肌I/R损伤中的作用。在12 - 15周龄的雄性C57 BL 6小鼠中，在I/R期间使用2种类型的p53抑制剂来抑制p53功能：pifithrin-α（p53转录功能的抑制剂）和pifithrin-m（p53从细胞质向线粒体易位的抑制剂）。无论是在缺血前还是在再灌注的前30分钟内输注这些抑制剂，都不能减少20分钟缺血/120分钟再灌注后的梗死面积。p53杂合敲除小鼠（p53+/-）和野生型小鼠（WT）的心肌细胞大小相似，但再灌注后120分钟，p53+/-小鼠的心率-压力乘积（RRP）恢复率高于WT。在基线条件下、缺血期间和再灌注开始后10分钟，WT中p53的蛋白表达可以忽略不计，但在再灌注后120分钟即可检测到。总之，尽管p53不参与缺血期间或再灌注早期的心肌细胞坏死，但再灌注后期p53的上调在再灌注后收缩功能障碍中发挥着重要作用。
p53 is well known as a regulator of apoptosis and autophagy. In addition, a recent study showed that p53 is a modulator of the opening of the mitochondrial permeability transition pore (mPTP), a trigger event of necrosis, but the role of p53 in necrosis induced by myocardial ischemia–reperfusion (I/R) remains unclear. The aim of this study was to determine the role of p53 in acute myocardial I/R injury in perfused mouse hearts. In male C57BL6 mice between 12 and 15 weeks of age, 2 types of p53 inhibitors were used to suppress p53 function during I/R: pifithrin-α, an inhibitor of transcriptional functions of p53, and pifithrin-m, an inhibitor of p53 translocation from the cytosol to mitochondria. Neither infusion of these inhibitors before ischemia nor infusion for the first 30-minute period of reperfusion reduced infarct size after 20-minute ischemia/120-minute reperfusion. Infarct sizes were similar in p53 heterozygous knockout mice (p53+/−) and wild-type mice (WT), but recovery of rate pressure product (RRP) 120 minutes after reperfusion was higher in p53+/−than in WT. The protein expression of p53 in WT was negligible under baseline conditions, during ischemia, and at 10 minutes after the start of reperfusion, but it became detectable at 120 minutes after reperfusion. In conclusion, upregulation of p53 during the late phase of reperfusion plays a significant role in contractile dysfunction after reperfusion, although p53 is not involved in cardiomyocyte necrosis during ischemia or in the early phase of reperfusion.
登录
查看更多内容
影响因子：
5.7
作者：
Pagel PS;Krolikowski JG;Pratt PF Jr;Shim YH;Amour J;Warltier DC;Weihrauch D
通讯作者：
Weihrauch D
影响因子：
64.8
作者：
Baines, CP;Kaiser, RA;Molkentin, JD
通讯作者：
Molkentin, JD
影响因子：
14.8
作者：
Strom, Evguenia;Sathe, Swati;Gudkov, Andrei V.
通讯作者：
Gudkov, Andrei V.
影响因子：
64.8
作者：
Sano, Masanori;Minamino, Tohru;Komuro, Issei
通讯作者：
Komuro, Issei
DOI：
10.1016/j.bbrc.2009.07.111
发表时间：
2009-10-02
影响因子：
3.1
作者：
Ferecatu, Ioana;Bergeaud, Marie;Vayssiere, Jean-Luc
通讯作者：
Vayssiere, Jean-Luc