title: All-Trans Retinoic Acid Ameliorates Myocardial Ischemia/Reperfusion Injury by Reducing Cardiomyocyte Apoptosis.
abstract: 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.
authors.affiliation: Department of Cardiology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China; Institute of Cardiovascular Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China.
authors.forename: Zhengbin
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Cardiology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China; Institute of Cardiovascular Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China.
authors.forename: Jinzhou
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Cardiology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China; Institute of Cardiovascular Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China.
authors.forename: Xiaoran
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Institute of Cardiovascular Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China.
authors.forename: Ke
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China; Institute of Cardiovascular Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Cardiology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China.
authors.forename: Fengru
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China; Institute of Cardiovascular Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China.
authors.forename: Weifeng
authors.initials: W
authors.lastname: Shen
authors.affiliation: Department of Cardiology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China; Institute of Cardiovascular Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China.
authors.forename: Ruiyan
authors.initials: R
authors.lastname: Zhang
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000494:pharmacology; D015687:Cell Hypoxia; D002460:Cell Line; D005434:Flow Cytometry; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D014212:Tretinoin; D051722:ADAM Proteins; D010100:Oxygen