Protective effects of Araloside C against myocardial ischaemia/reperfusion injury: potential involvement of heat shock protein 90

Abstract

The present study was designed to investigate whether Araloside C, one of the major triterpenoid compounds isolated from Aralia elata known to be cardioprotective, can improve heart function following ischaemia/reperfusion (I/R) injury and elucidate its underlying mechanisms. We observed that Araloside C concentration‐dependently improved cardiac function and depressed oxidative stress induced by I/R. Similar protection was confirmed in isolated cardiomyocytes characterized by maintaining Ca2+ transients and cell shortening against I/R. Moreover, the potential targets of Araloside C were predicted using the DDI‐CPI server and Discovery Studio software. Molecular docking analysis revealed that Araloside C could be stably docked into the ATP/ADP‐binding domain of the heat shock protein 90 (Hsp90) protein via the formation of hydrogen bonds. The binding affinity of Hsp90 to Araloside C was detected using nanopore optical interferometry and yielded KD values of 29 μM. Araloside C also up‐regulated the expression levels of Hsp90 and improved cell viability in hypoxia/reoxygenation‐treated H9c2 cardiomyocytes, whereas the addition of 17‐AAG, a pharmacologic inhibitor of Hsp90, attenuated Araloside C‐induced cardioprotective effect. These findings reveal that Araloside C can efficiently attenuate myocardial I/R injury by reducing I/R‐induced oxidative stress and [Ca2+]i overload, which was possibly related to its binding to the Hsp90 protein.

Araloside C Prevents Hypoxia/Reoxygenation-Induced Endoplasmic Reticulum Stress via Increasing Heat Shock Protein 90 in H9c2 Cardiomyocytes

“…We first detected the effects of AsC on HSP90 expression levels in H/R-treated H9c2 cardiomyocytes. Consistent with our previous reports ( Wang et al, 2017a ), AsC treatment significantly inhibited the H/R-induced down-regulation of HSP90 expression ( Figures 6A,B ).…”

“…A growing body of evidence implicates that HSP90 plays a critical role in the protective effect of myocardial ischemic preconditioning ( Jiao et al, 2008 ; Amour et al, 2009 ) and against I/R injury ( Kupatt et al, 2004 ; Zhu et al, 2016 ). Our oratory previously revealed that AsC was able to bind to the HSP90 protein in vitro in a dose-dependent manner with the KD 29 μM ( Wang et al, 2017a ).The current results confirmed that AsC significantly attenuated the apoptosis and the down-regulation of HSP90 expression induced by H/R H9c2 cardiomyocytes. By contrast, inhibition of HSP90 by 17-AAG, a well-known inhibitor of HSP90, notably blocked the AsC-induced cardioprotective effect against H/R injury ( Figures 6C – E ).…”

“…Araloside C was synthesized as previously reported ( Wang et al, 2017a ) at the Institute of Medicinal Plant Development (Beijing, China). Tunicamycin from Streptomyces was purchased from Sigma (St. Louis, MO, United States), and the 4-PBA (CAS.NO.…”

“…AsC ( Figure 2A ) is one of the most abundant triterpenoid compounds isolated from the bark and root of A. elata. Our group previously reported that AsC can improve heart function following I/R injury possibly by binding to the HSP90 protein ( Wang et al, 2017a ). However, the further cardioprotective properties and whether and how HSP90 is involved in the protective effects of AsC are still unknown.…”

Calenduloside E Analogues Protecting H9c2 Cardiomyocytes Against H2O2-Induced Apoptosis: Design, Synthesis and Biological Evaluation

“…The total saponins extracted from AS, which are found to be the main pharmacological active ingredients of AS, have been proved to exhibit anti-myocardial ischemic, anti-hypoxic activities, anti-oxidative as well as anti-inflammatory and anti-apoptotic capacity (Wang et al, 2003 ; Lee et al, 2009 ). We previously demonstrated that triterpenoid saponin Elatoside C and Araloside C from AS could protect the myocardial cells from ischaemia/reperfusion (IR) injury and reduce I/R-induced oxidative stress and apoptosis in cardiomyocytes (Wang et al, 2014b , 2015 , 2017 ). We also reported that the proteomic profiling of CE targets associated with anti-apoptosis effect in endothelia cells (Tian et al, 2017 ).…”