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

• DOI: 10.1371/journal.pone.0133414
• Publication Date: 2015-07-17T18:17:14Z
• Authors: Zhengbin Zhu; Jinzhou Zhu; Xiaoran Zhao; Ke Yang; Lin Lu; Fengru Zhang; Weifeng Shen; Ruiyan Zhang
• Keywords: Male; 0301 basic medicine; Cardiotonic Agents; MAP Kinase Signaling System; Science; Blotting, Western; Apoptosis; Myocardial Reperfusion Injury; Cell Line; 03 medical and health sciences; In Situ Nick-End Labeling; Animals; Myocytes, Cardiac; Mice, Knockout; Myocardium; Q; R; Heart; Flow Cytometry; Cell Hypoxia; Rats; 3. Good health; Mice, Inbred C57BL; Oxygen; ADAM Proteins; Medicine; Reactive Oxygen Species; Research Article

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.