Transduction of anti-cell death protein FNK protects isolated rat hearts from myocardial infarction induced by ischemia/reperfusion
Transduction of anti-cell death protein FNK protects isolated rat hearts from myocardial infarction induced by ischemia/reperfusion
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DOI：
10.1016/j.lfs.2007.03.012
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发表时间：
2007-05-08
期刊：
影响因子：
6.1
通讯作者：
Ohta, Shigeo
中科院分区：
文献类型：
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作者：
Arakawa, Masayuki;Yasutake, Masahiro;Ohta, Shigeo
人工抗细胞死亡蛋白FNK是一种Bcl-x(L)衍生物，具有三个氨基酸取代（Y22F， Q26N和R165K），具有增强抗凋亡和抗坏死活性，促进许多物种和细胞类型的细胞存活。本研究的目的是(i)研究与蛋白转导结构域（PTD-FNK）结合的蛋白是否能减少缺血/再灌注大鼠心肌梗死面积并改善缺血后心功能，以及（ii）了解PTD-FNK发挥保护作用的机制。采用Langendorff法对离体大鼠心脏进行35分钟全脑缺血，然后120分钟再灌注。将PTD-FNK分别于全缺血诱导后1 min （a组）或全缺血诱导后30 min（再灌注前5 min）（13组）肌内注射至左心室前壁，共30 91例。在A组，PTD-FNK浓度分别为5、50和500 nmol/l时，梗死面积从对照组的47.8 +/- 6.8%显著降低至30.4 +/- 5.2、28.7 +/- 3.8和30.4 +/- 6.8% （p < 0.05）。PTD-FNK（50和500 nmol/l）处理组在再灌注后60 min和120 min左室发育压的时间恢复明显优于对照组（p < 0.05）。与此相反，PTD-FNK处理对b组没有影响。Western blot分析显示，PTD-FNK显著抑制procaspase-3的裂解（caspase-3的激活），并减少了末端脱氧核苷酸转移酶介导的5-三磷酸脱氧尿苷镍端标记（TUNEL）法染色的细胞核数量。这些发现表明，PTD-FNK至少在一定程度上通过抑制缺血/再灌注后的心肌凋亡来减少心肌梗死的体积并相应的功能恢复。(c) 2007爱思唯尔公司版权所有。
Artificial anti-cell death protein FNK, a Bcl-x(L) derivative with three amino acid-substitutions (Y22F, Q26N, and R165K) has enhanced antiapoptotic and anti-necrotic activity and facilitates cell survival in many species and cell types. The objectives of this study were (i) to investigate whether the protein conjugated with a protein transduction domain (PTD-FNK) reduces myocardial infarct size and improves post-ischemic cardiac function in ischemic/reperfused rat hearts, and (ii) to understand the mechanism(s) by which PTD-FNK exerts a protective effect. Isolated rat hearts were subjected to 35-min global ischemia, followed by 120-min reperfusion using the Langendorff methods. PTD-FNK (a total of 30 91) was injected intramuscularly into the anterior wall of the left ventricle either at 1 min after induction of global ischemia (group A) or at 30 min after induction of global ischemia (at 5 min before reperfusion) (group 13). In group A, infarct size was significantly reduced from 47.8 +/- 6.8% in the control to 30.4 +/- 5.2, 28.7 +/- 3.8, and 30.4 +/- 6.8% with PTD-FNK at 5, 50, and 500 nmol/l, respectively (p < 0.05). Temporal recovery of left ventricular developed pressure at 60 min and 120 min after reperfusion was significantly better in PTD-FNK (50 and 500 nmol/l)-treated groups than in the control (p < 0.05). In contrast, PTD-FNK treatment had no effect on group B. Western blot analysis showed that PTD-FNK markedly inhibited procaspase-3 cleavage (activation of caspase-3) and reduced the number of nuclei stained by a terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphoshate nick-end labeling (TUNEL) assay. These findings suggest that PTD-FNK reduces the volume of myocardial infarction with corresponding functional recovery, at least in part, through the suppression of myocardial apoptosis following ischemia/reperfusion. (c) 2007 Elsevier Inc. All rights reserved.