Elatoside C protects the heart from ischaemia/reperfusion injury through the modulation of oxidative stress and intracellular Ca2 + homeostasis

doi:10.1016/j.ijcard.2015.03.140

International Journal of Cardiology

Volume 185, 15 April 2015, Pages 167-176

https://doi.org/10.1016/j.ijcard.2015.03.140 Get rights and content

Abstract

Background

We have previously shown that Elatoside C reduces cardiomyocyte apoptosis during ischaemia/reperfusion (I/R). Here, we investigated whether Elatoside C improves heart function in isolated rat hearts subjected to I/R and elucidated the potential mechanisms involved in Elatoside C-induced protection.

Methods and results

Isolated rat hearts were subjected to global ischaemia followed by reperfusion in the absence or presence of Elatoside C. We found that Elatoside C significantly attenuated cardiac dysfunction and depressed oxidative stress induced by I/R. Consistently, Elatoside C prevented I/R-induced mitochondrial dysfunction, which was evident by the inhibition of mitochondrial ROS production, mitochondrial permeability transition pore (mPTP) opening, cytochrome c release from the mitochondria and Bax translocation. Moreover, Elatoside C improved abnormal calcium handling during I/R, including increasing sarcoplasmic reticulum Ca^2 + ATPase (SERCA2) activity, alleviating [Ca^2 +]_ER depletion, and reducing the expression levels of ER stress protein markers. All of these protective effects of Elatoside C were partially abolished by the PI3K/Akt inhibitor LY294002, ERK1/2 inhibitor PD98059, and JAK2/STAT3 inhibitor AG490. Further assessment in isolated cardiomyocytes showed that Elatoside C maintained the Ca^2 + transients and cell shortening against I/R.

Conclusions

Elatoside C protects against cardiac injury during I/R by attenuating oxidative stress and [Ca^2 +]_i overload through the activation of both the reperfusion injury salvage kinase (RISK) pathway (including PI3K/Akt and ERK1/2) and the survivor activating factor enhancement (SAFE) pathway (including JAK2/STAT3) and, subsequently, inhibiting the opening of mPTPs.

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 Ca^2 + handling by depressing endoplasmic reticulum/sarcoplasmic reticulum (ER/SR) Ca^2 + 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 Ca^2 + 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 Ca^2 + 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 Ca^2 + 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.

Section snippets

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/dt_max, 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 Ca^2 + 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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Redox regulation of cardiac calcium channels and transporters
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Mitochondrial depolarization underlies delay in permeability transition by preconditioning with isoflurane: roles of ROS and Ca^2 +
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The SR–mitochondria interaction: a new player in cardiac pathophysiology
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Effect of three triterpenoid compounds isolated from root bark of Aralia elata on stimulus-induced superoxide generation and tyrosyl phosphorylation and translocation of p47(phox) and p67(phox) to cell membrane in human neutrophil

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Elatoside C protects the heart from ischaemia/reperfusion injury through the modulation of oxidative stress and intracellular Ca2 + homeostasis

Abstract

Background

Methods and results

Conclusions

Introduction

Section snippets

Animals

Elatoside C improved cardiac function of the I/R hearts

Discussion

Conflict of interest

Acknowledgements

Targeting reperfusion injury in acute myocardial infarction: a review of reperfusion injury pharmacotherapy

Expert. Opin. Pharmacother.

Cell biology of ischemia/reperfusion injury

Int. Rev. Cell Mol. Biol.

Slow calcium waves and redox changes precede mitochondrial permeability transition pore opening in the intact heart during hypoxia and reoxygenation

Cardiovasc. Res.

Redox regulation of cardiac calcium channels and transporters

Cardiovasc. Res.

Apelin protects sarcoplasmic reticulum function and cardiac performance in ischaemia–reperfusion by attenuating oxidation of sarcoplasmic reticulum Ca2 +-ATPase and ryanodine receptor

Cardiovasc. Res.

Ranolazine reduces Ca2 + overload and oxidative stress and improves mitochondrial integrity to protect against ischemia reperfusion injury in isolated hearts

Pharmacol. Res.

Mitochondrial depolarization underlies delay in permeability transition by preconditioning with isoflurane: roles of ROS and Ca2 +

Am. J. Physiol. Cell Physiol.

The SR–mitochondria interaction: a new player in cardiac pathophysiology

Cardiovasc. Res.

Breakthrough solutions in herbal medicine adaptogenic formulas: the way to vitality

Medicinal uses of ginseng and related plants in the Soviet Union: recent trends in the Soviet literature

J. Ethnopharmacol.

Protective effects of aralosides on cultured myocardial cells subjected to anoxia/reoxygenation injury

Chin. Pharmacol. Bull.

Protective effect of aralosides of Aralia elata on experimental myocardial ischemia of rats

Chin. J. Pharmacol.

Effect of the total saponins of Aralia elata (Miq) Seem on cardiac contractile function and intracellular calcium cycling regulation

J. Ethnopharmacol.

Effect of three triterpenoid compounds isolated from root bark of Aralia elata on stimulus-induced superoxide generation and tyrosyl phosphorylation and translocation of p47(phox) and p67(phox) to cell membrane in human neutrophil

Clin. Chim. Acta

Elatoside C protects against hypoxia/reoxygenation-induced apoptosis in H9c2 cardiomyocytes through the reduction of endoplasmic reticulum stress partially depending on STAT3 activation

Apoptosis

Reperfusion injury salvage kinase and survivor activating factor enhancement prosurvival signaling pathways in ischemic postconditioning: two sides of the same coin

Antioxid. Redox Signal.

New directions for protecting the heart against ischaemia–reperfusion injury: targeting the reperfusion injury salvage kinase (RISK)-pathway

Cardiovasc. Res.

Activation of the protective survivor activating factor enhancement (SAFE) pathway against reperfusion injury: does it go beyond the RISK pathway?

J. Mol. Cell. Cardiol.

Elatoside C protects the heart from ischaemia/reperfusion injury through the modulation of oxidative stress and intracellular Ca^2 + homeostasis

Apelin protects sarcoplasmic reticulum function and cardiac performance in ischaemia–reperfusion by attenuating oxidation of sarcoplasmic reticulum Ca^2 +-ATPase and ryanodine receptor

Ranolazine reduces Ca^2 + overload and oxidative stress and improves mitochondrial integrity to protect against ischemia reperfusion injury in isolated hearts

Mitochondrial depolarization underlies delay in permeability transition by preconditioning with isoflurane: roles of ROS and Ca^2 +