Elatoside C protects the heart from ischaemia/reperfusion injury through the modulation of oxidative stress and intracellular Ca2 + homeostasis
Introduction
Ischaemia/reperfusion (I/R) injury is a major clinical problem that causes increased myocardial dysfunction and further cardiomyocyte death after cardiac surgery and myocardial infarctions [1]. The mechanisms of I/R injury are complex and mainly include excessive ROS production and intracellular calcium overload [2], [3]. Recent studies show that these mechanisms are interrelated with each other, where ROS overproduction can induce abnormal Ca2 + handling by depressing endoplasmic reticulum/sarcoplasmic reticulum (ER/SR) Ca2 + uptake and release activities [4], [5]. In turn, dramatic increases in cytosolic calcium concentrations can enhance ROS production [6], [7]. A substantial rise in ROS and Ca2 + release associated with I/R triggers contractile abnormalities and massive opening of the mitochondrial permeability transition pore (mPTP), whose opening eventually leads to cell death [3], [8]. Thus, the disruption of this vicious cycle of damage by an excess of ROS production and Ca2 + overload during I/R may have important implications in reducing cardiac injury.
Aralia elata (Miq) Seem, a well-known adaptogenic plant, has been traditionally used as a tonic medicine to increase energy and improve the body's hypoxia ability [9], [10]. The total saponins of A. elata (AS), which are considered as the main pharmacologically active ingredient extracted from A. elata, have been shown to exhibit anti-myocardial ischaemic and anti-hypoxic activities [11], [12]. Moreover, A. elata Xinmaitong capsules (Clinical Trial Approval Number 2003L01111), which we developed for the treatment of coronary heart disease, are mainly composed of AS and have successfully completed Phase III clinical trials in China [13]. Thus, it is interesting to further explore the cardio-protective potentials of the active compound from AS. Elatoside C (Supplementary material, Supplementary Fig. 1) is one of the major triterpenoid saponins in AS [14]. A previous report demonstrated that it has strong anti-superoxide activity [14]. We recently found that Elatoside C can alleviate hypoxia/reoxygenation (H/R)-induced cardiomyocyte apoptosis [15]. However, the effects of Elatoside C on I/R injury in isolated perfused hearts remain unknown.
Great attention has focused on the innate protective pathways, such as the reperfusion injury salvage kinases (RISKs) and survivor activating factor enhancement (SAFE) pathways, which confer myocardial protection against I/R injury [1], [16]. The RISK pathway involves the kinases Akt and ERK1/2 [17]. Janus kinase/signal transducer and activator of transcription (JAK2/STAT3) signalling is part of the SAFE pathway [18]. All of these pathways have been suggested to converge on the mitochondria to inhibit the open probability of the mPTP and to mediate protection [16]. Elatoside C was found to protect cultured cardiomyocytes against hypoxia/reoxygenation injury via the activation of the STAT3 pathway [15]. Whether these signalling pathways contribute to the cardioprotection of Elatoside C against I/R in hearts, however, has not been investigated.
Therefore, the aim of the present study was to (1) evaluate whether Elatoside C would improve cardiac dysfunction in I/R hearts; (2) investigate the potential effects of Elatoside C on oxidative stress and abnormal Ca2 + regulation by I/R injury; and (3) determine the roles of the SAFE and RISK signalling components, such as JAK2/STAT3, Akt and ERK1/2, in Elatoside C-induced cardioprotection.
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Animals
Male Sprague–Dawley rats (180 g to 250 g) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., Beijing, China. The animals were housed under standard laboratory conditions (25 ± 1 °C, 60% humidity, with a 12 h photoperiod) and provided free access to sterile food and water. All of the procedures were approved by the Laboratory Animal Ethics Committee of the Institute of Medicinal Plant Development, Peking Union Medical College, and conformed to the Guide for the Care and
Elatoside C improved cardiac function of the I/R hearts
In the present study, compared with the I/R group, Elatoside C from 2 to 50 nmol/L concentration dependently improved the functional recovery of the I/R hearts, which was demonstrated by significant increases in LVSP, ± dP/dtmax, and heart rate throughout the reperfusion period, although the baseline mechanical parameters with Elatoside C were not significantly different compared with those of the control condition (Fig. 1A–D). Next, we investigated whether Elatoside C affects myocardial injury
Discussion
Elatoside C, a major triterpenoid saponin of A. elata, has been known to possess antioxidant and anti-H/R properties [14], [15]. However, the cardioprotective effects of Elatoside C on I/R hearts are largely unknown. In the present study, we found that Elatoside C suppresses cardiac dysfunction during I/R. Furthermore, Elatoside C depresses oxidative stress and mitochondrial injury induced by I/R. On the other hand, Elatoside C attenuates I/R-induced abnormal Ca2 + handling and ER stress related
Conflict of interest
The authors report no relationships that could be construed as a conflict of interest.
Acknowledgements
This study was supported by the National Natural Science Foundation of China (Grant Nos. 81173589 and 81473380), the Natural Science Foundation of Beijing (Grant No. 7142108), the Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant No. 20121106110033), and the Program for Innovative Research Team in IMPLAD (Grant No. IT1301).
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