All-Trans Retinoic Acid Ameliorates Myocardial Ischemia/Reperfusion Injury by Reducing Cardiomyocyte Apoptosis

作者：Zhu, Zhengbin; Zhu, Jinzhou; Zhao, Xiaoran; Yang, Ke; Lu, Lin; Zhang, Fengru; Shen, Weifeng; Zhang, Ruiyan^*

来源：PLos One, 2015, 10(7): e0133414.

DOI：10.1371/journal.pone.0133414

• ACTIVATED PROTEIN-KINASE
• REPERFUSION INJURY
• EXPRESSION
• MECHANISM
• ISCHEMIA
• INHIBITION
• RECEPTORS
• PATHWAYS
• ADAM10
• RAGE

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.

• 出版日期2015-7-17
• 单位上海交通大学; 上海市闵行区中心医院