Abstract
Ginsenoside Rg1, a saponin that is a primary component of ginseng, has been demonstrated to protect hearts from diverse cardiovascular diseases with regulating multiple cellular signal pathways. In the present study, we investigated the protective role of ginsenoside Rg1 on doxorubicin-induced cardiotoxicity and its effects on endoplasmic reticulum stress and autophagy. After pre-treatment with ginsenoside Rg1 (50 mg/kg i.g.) for 7 days, male C57BL/6J mice were intraperitoneally injected with a single dose of doxorubicin (6 mg/kg) every 3 days for four injections. Echocardiographic and pathological findings showed that ginsenoside Rg1 could significantly reduce the cardiotoxicity induced by doxorubicin. Ginsenoside Rg1 significantly inhibited doxorubicin-induced formation of autophagosome. At the same time, ginsenoside Rg1 decreased the doxorubicin-induced cardiac microtubule-associated protein-light chain 3 and autophagy related 5 expression. Ginsenoside Rg1 can reduce endoplasmic reticulum dilation caused by doxorubicin. Compared with the doxorubicin group, the expression of cleaved activating transcription factor 6 and inositol-requiring enzyme 1 decreased in group ginsenoside Rg1. Treatment with ginsenoside Rg1 reduces the expression of TIF1 and increases the expression of glucose-regulated protein 78. In the ginsenoside Rg1 group, the expression of p-P70S6K, c-Jun N-terminal kinases 1 and Beclin1 declined. These results indicate that ginsenoside Rg1 may improve doxorubicin-induced cardiac dysfunction by inhibiting endoplasmic reticulum stress and autophagy.
Highlights
Doxorubicin is a widely used and highly successful anticancer chemotherapeutic drugs agent
Hematoxylin-eosin (HE) results showed that DOX-treated hearts displayed myofibrillar degeneration and disruption when compared with normal control hearts (Figure 2)
Ginsenoside Rg1 treatment can significantly improve the defects induced by DOX
Summary
Doxorubicin is a widely used and highly successful anticancer chemotherapeutic drugs agent. It is well established that cancer patients undergoing doxorubicin treatment are susceptible to cardiac anomalies, including hypotension, tachycardia, arrhythmia, and transient depression of left ventricular function [2]. A major challenge in managing cancer patients treated with doxorubicin is to minimize doxorubicin’s cardiotoxic effects without compromising its antitumor properties. Autophagy is a conserved process aimed at maintaining cell and tissue homeostasis by degrading and recycling macromolecules, organelles and nutrients. The accumulation of oxidized and damaged macromolecules and organelles induced by doxorubicin can lead to autophagy in cardiac myocytes [4]. It has been reported that the suppression of autophagy could attenuate doxorubicin-induced cardiotoxicity [5,6,7]. Pharmacologic inhibition of post- doxorubicin (DOX) autophagy by 3-methyladenine protected cardiac cells from DOX toxicity [4]. Decrease of autophagy could be a potential strategy for the treatment of DOX-induced cardiomyopathy
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