Inhibition of myocardial apoptosis reduces infarct size and improves regional contractile dysfunction during reperfusion
Inhibition of myocardial apoptosis reduces infarct size and improves regional contractile dysfunction during reperfusion
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DOI：
10.1016/s0008-6363(03)00344-4
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发表时间：
2003-07-01
影响因子：
10.8
通讯作者：
Guyton, RA
中科院分区：
文献类型：
--
作者：
Zhao, ZQ;Morris, CD;Guyton, RA
目的：心肌细胞凋亡主要是在再灌注（R）期间通过各种机制触发的，这些机制可能涉及核酸内切酶切割核小体间连接区的基因组DNA。然而，心肌细胞凋亡的相对贡献，在R期间心肌损伤的发展仍然是未知的。在本研究中，我们研究了在R期间用金精三羧酸（ATA）（一种核酸内切酶抑制剂）抑制细胞凋亡是否可以减少梗死面积并改善局部收缩功能。方法和结果：在两组慢性内固定犬中，左前降支（LAD）冠状动脉闭塞1 h后进行24 h R，并在R前5 min开始向左心房输注生理盐水（对照，n = 8）或ATA（1 mg/kg/h，n = 8），持续2 h。ATA显著减少了坏死周围心肌中的凋亡细胞（TUNEL染色）（12 +/-1%* 对比36 +/-4%），与不存在DNA梯状化一致。为了证实ATA对细胞凋亡的抑制作用，采用光密度法，Bcl-2（正常心肌%）与对照组相比显著增加（102 +/-12 * vs. 68 +/-9）和Bax以及活化的半胱天冬酶-3与对照组相比显著降低（分别为108 +/-17 * vs. 194 +/-42和-29 +/-4 * vs. 174 +/-43）。ATA显著改善节段性缩短（3.3 +/-1.2 * vs.-1.8 +/-0.7%）和分段工作（危险心肌区为79.3 +/-11.3 * vs. 7.1 +/-5.8 mmHg/mm，梗死面积减少（TTC染色，27 +/-0.2 * vs. 37 - 1 - 0.5%），证实了较低的血浆肌酸激酶活性。此外，心肌血流量（0.9 +/-0.1 * vs. 0.4 +/-0.1 ml/min/g）和内皮依赖性最大血管舒张（119 +/-6 * vs. 49 +/-8%）显著改善。危险心肌区的髓过氧化物酶活性（中性粒细胞蓄积的标志物）也显著降低（17 +/-4 * vs. 138 +/-28 DeltaAb/mim.结论：这些数据表明，抑制细胞凋亡在R与减少梗死，改善区域收缩和血管内皮功能，以及增加心肌血流量。* P <0.05与对照组相比。(C)2003年欧洲心脏病学会。由Elsevier Science B.V.出版，版权所有。
Objective: Myocardial apoptosis is primarily triggered during reperfusion (R) through various mechanisms that may involve endonuclease to cleavage genomic DNA in the internucleosomal linker regions. However, the relative contribution of myocardial apoptosis to development of myocardial injury during R remains unknown. In the present study, we examined whether inhibition of apoptosis with aurintricarboxylic acid (ATA), an endonuclease inhibitor, during R reduces infarct size and improves regional contractile function. Methods and Results: In two groups of chronically-instrumented dogs, 1 h of left anterior descending (LAD) coronary occlusion was followed by 24 h of R with infusion of saline (control, n = 8) or ATA (1 mg/kg/h, n = 8) into the left atrium starting 5 min before R and continuing for 2 h. ATA significantly reduced apoptotic cells (TUNEL staining) in the peri-necrotic myocardium ( 12 +/- 1 %* vs. 36 +/- 4%), consistent with the absence of DNA laddering. To confirm inhibition of apoptosis with ATA, densitometrically, Bcl-2 (% of normal myocardium) was significantly increased vs. control (102 +/- 12* vs. 68 +/- 9) and Bax as well as the activated caspase-3 were significantly reduced vs. control ( 108 +/- 17* vs. 194 +/- 42 and -29 +/- 4* vs. 174 +/- 43, respectively). ATA significantly improved segmental shortening (3.3 +/- 1.2* vs. -1.8 +/- 0.7%) and segmental work (79.3 +/- 11.3* vs. 7.1 +/- 5.8 mmHg/mm in area at risk myocardium, and reduced infarct size (TTC staining, 27 +/- 0.2* vs. 37-1-0.5%), confirmed by lower plasma creatine kinase activity. In addition, myocardial blood flow (0.9 +/- 0.1* vs. 0.4 +/- 0.1 ml/min/g) and endothelial-dependent maximal vascular relaxation (119 +/- 6* vs. 49 +/- 8%) were significantly improved. Myeloperoxidase activity in area at risk myocardium, a marker for neutrophil accumulation, was also significantly reduced (17 +/- 4* vs. 138 +/- 28 DeltaAbs/mim. Conclusions: These data suggest that the inhibition of apoptosis during R is associated with a reduction in infarction, improvement in regional contractile and vascular endothelial functions as well as augmentation in myocardial blood flow. *P < 0.05 vs. control group. (C) 2003 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.