All-Trans Retinoic Acid Ameliorates Myocardial Ischemia/Reperfusion Injury by Reducing Cardiomyocyte Apoptosis.
All-Trans Retinoic Acid Ameliorates Myocardial Ischemia/Reperfusion Injury by Reducing Cardiomyocyte Apoptosis.
复制标题
全反式视黄酸通过减少心肌细胞凋亡来改善心肌缺血/再灌注损伤。
DOI：
10.1371/journal.pone.0133414
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Zhang R
中科院分区：
文献类型：
--
作者：
Zhu Z;Zhu J;Zhao X;Yang K;Lu L;Zhang F;Shen W;Zhang R
心肌缺血/再灌注（I/R）损伤干扰缺血心肌的血流恢复。氧化应激引起的细胞凋亡已被报道有助于I/R损伤。全反式维甲酸（ATRA）具有抗凋亡活性，如先前所报道的。本研究探讨了全反式维甲酸（ATRA）对离体及在体心肌I/R损伤的影响及其作用机制。在体实验中，ATRA可缩小心肌梗死面积（17.81±1.05% vs.24.41 ± 1.03%，P<0.05），并可挽救心功能（射血分数46.42±6.76% vs.37.18 ± 4.63%，P<0.05）。流式细胞术和TUNEL法证实ATRA对心肌I/R损伤的保护作用与其抗凋亡作用有关。ATRA的抗凋亡作用与部分抑制活性氧（ROS）的产生和显着减少磷酸化的丝裂原活化蛋白激酶（MAPK），包括p38，JNK和ERK。Western blot分析还显示，ATRA预处理增加了含去整合素和金属蛋白酶结构域的蛋白10（ADAM 10）的表达（体内0.65 ± 0.20 vs.0.41 ±0.02），并降低了晚期糖基化终产物（AGEs）受体的水平（体内0.38 ± 0.17 vs.0.52 ± 0.11）。同时，ATRA对RAGE-KO小鼠的I/R损伤没有保护作用。目前的研究结果表明，ATRA可以有效地预防I/R后心肌损伤，减少心肌细胞凋亡。ATRA可能通过增加心肌I/R损伤中MAPK上游受体ADAM 10的表达，从而下调MAPK信号通路，对心肌I/R损伤起到保护作用。
Myocardial ischemia/reperfusion (I/R) injury interferes with the restoration of blood flow to ischemic myocardium. Oxidative stress-elicited apoptosis has been reported to contribute to I/R injury. All-trans retinoic acid (ATRA) has anti-apoptotic activity as previously reported. Here, we investigated the effects and the mechanism of action of ATRA on myocardial I/R injury both in vivo and in vitro. In vivo, ATRA reduced the size of the infarcted area (17.81±1.05% vs. 24.41±1.03%, P<0.05) and rescued cardiac function loss (ejection fraction 46.42±6.76% vs. 37.18±4.63%, P<0.05) after I/R injury. Flow-cytometric analysis and TUNEL assay demonstrated that the protective role of ATRA on myocardial I/R injury was related to its anti-apoptotic effects. The anti-apoptotic effects of ATRA were associated with partial inhibition of reactive oxygen species (ROS) production and significantly less phosphorylation of mitogen-activated protein kinases (MAPKs) including p38, JNK, and ERK. Western blot analysis also revealed that ATRA pre-treatment increased a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) expression (0.65 ± 0.20 vs. 0.41±0.02 in vivo) and reduced the level of receptor for advanced glycation end-products (RAGE) (0.38 ± 0.17 vs. 0.52 ± 0.11 in vivo). Concomitantly, the protective role of ATRA on I/R injury was not observed in RAGE-KO mice. The current results indicated that ATRA could prevent myocardial injury and reduced cardiomyocyte apoptosis after I/R effectively. One possible mechanism underlying these effects is that ATRA could increase ADAM10 expression and thus cleave RAGE, which is the main receptor up-stream of MAPKs in myocardial I/R injury, resulting in the down-regulation of MAPK signaling and protective role on myocardial I/R injury.