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.

The role of retinoids in acute renal damage associated with acetic acid induced ulcerative colitis in adult male rats : Histological and biochemical study

“…In the present study, RP and ATRA markedly diminished the apoptosis in renal tubules that showed reduction in apoptoyic cells and immunohistchemical staining of BAX. These findings are consistent with previous reports that described the inhibition of retinoids for apoptosis in myocardial ischemia/reperfusion injury and neuronal cells [49,50] . The attenuation of renal apoptosis can be attributed to the observed reduction of oxidative stress [48] .…”

The RhoA/ROCK pathway mediates high glucose‐induced cardiomyocyte apoptosis via oxidative stress, JNK, and p38MAPK pathways

“…MAPK activation has also been implicated in the pathogenesis of DCM. It has been reported that activation of MAPK signalling, specifically p38MAPK and JNK, is relevant to the regulation of myocardial apoptosis during ischemia/reperfusion injury . There are abundant data that imply the role of HG‐induced oxidative stress in the activation of MAPKs.…”

ADAM10 modulates calcitriol‐regulated RAGE in cardiomyocytes

“…ADAM10, a metalloprotease, functions primarily in cleaving the extracellular domains of various cell surface molecules, including RAGE [10,11]. A study demonstrated that ADAM10 upregulation reduced RAGE expression, contributing to decreased cardiomyocyte apoptosis after ischaemic reperfusion injury [27]. Clinical investigation showed that patients with type 1 DM had higher serum ADAM10 with a significant association between serum ADAM10 and sRAGE [28].…”