Tilianin Protects against Ischemia/Reperfusion-Induced Myocardial Injury through the Inhibition of the Ca2+/Calmodulin-Dependent Protein Kinase II-Dependent Apoptotic and Inflammatory Signaling Pathways.

Zhuorong Li,Jianguo Xing,Jiansong Fang,Rui Liu,Li Zeng,Hailun Jiang,Yu Wang,Linlin Wang

doi:10.1155/2020/5939715

Abstract

Tilianin is a naturally occurring phenolic compound with a cardioprotective effect against myocardial ischemia/reperfusion injury (MIRI). The aim of our study was to determine the potential targets and mechanism of action of tilianin against cardiac injury induced by MIRI. An in silico docking model was used in this study for binding mode analysis between tilianin and Ca2+/calmodulin-dependent protein kinase II (CaMKII). Oxygen-glucose deprivation/reperfusion- (OGD/R-) injured H9c2 cardiomyocytes and ischemia/reperfusion- (I/R-) injured isolated rat hearts were developed as in vitro and ex vivo models, respectively, which were both treated with tilianin in the absence or presence of a specific CaMKII inhibitor KN93 for target verification and mechanistic exploration. Results demonstrated the ability of tilianin to facilitater the recovery of OGD/R-induced cardiomyocyte injury and the maintenance of cardiac function in I/R-injured hearts. Tilianin interacted with CaMKIIδ with an efficient binding performance, a favorable binding score, and restraining p-CaMKII and ox-CaMKII expression in cardiomyocytes injured by MIRI. Importantly, inhibition of CaMKII abolished tilianin-mediated recovery of OGD/R-induced cardiomyocyte injury and maintenance of cardiac function in I/R-injured hearts, accompanied by the disability to protect mitochondrial function. Furthermore, the protective effects of tilianin towards mitochondrion-associated proapoptotic and antiapoptotic protein counterbalance and c-Jun N-terminal kinase (JNK)/nuclear factor- (NF-) κB-related inflammation suppression were both abolished after pharmacological inhibition of CaMKII. Our investigation indicated that the inhibition of CaMKII-mediated mitochondrial apoptosis and JNK/NF-κB inflammation might be considered as a pivotal mechanism used by tilianin to exert its protective effects on MIRI cardiac damage.

Highlights

Cardiac reperfusion following acute myocardial ischemia, known as myocardial ischemia/reperfusion injury (MIRI), contributes to cardiomyocyte damage
The present study is aimed at verifying the involvement and function of calmodulin-dependent protein kinase II (CaMKII) on the mitochondrion-associated apoptotic pathway and MAPK/nuclear factor- (NF-)κB-related inflammatory reaction in the protection exerted by tilianin against MIRI
Tilianin was identified as a potential CaMKII inhibitor because it prevented I/R-induced myocardial dysfunction both in vitro and ex vivo

Summary

Introduction

Cardiac reperfusion following acute myocardial ischemia, known as myocardial ischemia/reperfusion injury (MIRI), contributes to cardiomyocyte damage. CaMKII is located in the mitochondria of cardiomyocytes. During postischemic reperfusion, both cellular Ca2+ and ROS activate CaMKII by binding with diverse activation sites and to a greater extent in the initial period of reperfusion [2,3,4,5]. The phosphorylation and oxidation of CaMKII induce mitochondrial damage and regulate critical proteins related to the apoptotic and inflammatory progress due to MIRI [6,7,8,9,10]. CaMKII may represent an attractive target for reducing mitochondrial dysfunction and inflammatory response induced by MIRI

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