The Anti-Apoptotic and Cardioprotective Effects of Salvianolic Acid A on Rat Cardiomyocytes following Ischemia/Reperfusion by DUSP-Mediated Regulation of the ERK1/2/JNK Pathway

Xu, Tongda; Wu, Xin; Chen, Qiuping; Zhu, Shasha; Yang, Lizhu; Pan, Defeng; Chen, Xiaohu; Li, Dongye

doi:10.1371/journal.pone.0102292

Cited by 48 publications

(43 citation statements)

References 31 publications

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“…Previous studies have demonstrated that oxidative stress induced the activation of MAPK pathways, but there are conflicting reports about their specific effects on oxidative stress [45,46,47]. The ERK pathway is usually thought to deliver survival signals that protect cells from apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Studies have demonstrated that the expression of p-ERK1/2 was increased during IR injury in the myocardium and cerebrum [45,47]. However, Xu et al [46] showed that the expression of p-ERK1/2 in the myocardium in the IR group was not significantly different compared with the control group during IR. In our previous work, crocin activated the p-AKT signaling pathway to inhibit GCL apoptosis in IR rats [22].…”

Section: Discussionmentioning

confidence: 99%

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Neuroprotective Effects of Crocin against Oxidative Stress Induced by Ischemia/Reperfusion Injury in Rat Retina

Chen

Yang

2015

Ophthalmic Res

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Aims: Crocin, a pharmacologically active component of Crocus sativus L. (saffron), has been reported to be useful in the treatment of oxidative stress injury. In the present study, we investigated the antioxidative effect of crocin and the change of the ERK signaling pathway on rat retina induced by ischemia/reperfusion (IR) injury. Methods: Crocin was pretreated 30 min before and once daily after retinal IR injury by intraperitoneal injection. The retinal morphological damage was observed by hematoxylin and eosin (HE) staining. The number of retinal ganglion cells (RGCs) was counted by Brn-3a immunofluorescence staining. The antiapoptotic effect of crocin was determined by detecting cleaved caspase-3 protein levels by means of Western blot and immunohistochemical analysis. Furthermore, retinas were also used for the determination of malondialdehyde (MDA) levels, glutathione (GSH) levels, total superoxide dismutase (T-SOD), and reactive oxygen species (ROS). The phosphorylated ERK (p-ERK) protein level was determined by Western blot and immunohistochemical analysis. Results: Our results showed that crocin treatment (50 mg/kg) significantly inhibited the decrease of retinal thickness through HE staining and protected RGCs from decreasing. Compared with the IR + vehicle group, crocin treatment significantly decreased cleaved caspase-3 and p-ERK protein expression by Western blot analysis and immunohistochemistry. Immunohistochemical staining for cleaved caspase-3 and p-ERK in the retinal sections showed positive cells were present in the RGC layer and inner nuclear layer after IR injury. Similarly, crocin (50 mg/kg) treatment also significantly increased the level of activity of GSH, enhanced the activity of T-SOD, and decreased the activity level of ROS and MDA after IR injury. Conclusions: These findings demonstrated that crocin treatment could notably protect the retina from damage induced by IR. It might be related to crocin antioxidant and antiapoptotic properties in the retina.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effects of Crocin against Oxidative Stress Induced by Ischemia/Reperfusion Injury in Rat Retina

Chen

Yang

2015

Ophthalmic Res

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“…This agent is broadly used as a clinical drug to treat cardiovascular diseases [13] . Salvianolic acid A (SAA) ((2R)-3-(3,4-dihydroxyphenyl)-2-[(E)-3-[2-[(E)-2-(3,4-dihy-droxyphenyl)ethenyl]-3,4-dihydroxyphenyl]prop-2-enoyl] oxypropanoic acid) is one of the most bioactive compounds in S miltiorrhiza and exhibits many pharmacological activities, including antioxidation, myocardial protection, antithrombosis, antifibrosis, and the prevention of diabetes complications [14] .…”

Section: Introductionmentioning

confidence: 99%

Salvianolic acid A attenuates vascular remodeling in a pulmonary arterial hypertension rat model

Chen¹,

Yuan²,

Zhang³

et al. 2016

Acta Pharmacol Sin

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Aim:The current therapeutic approaches have a limited effect on the dysregulated pulmonary vascular remodeling, which is characteristic of pulmonary arterial hypertension (PAH). In this study we examined whether salvianolic acid A (SAA) extracted from the traditional Chinese medicine 'Dan Shen' attenuated vascular remodeling in a PAH rat model, and elucidated the underlying mechanisms. Methods: PAH was induced in rats by injecting a single dose of monocrotaline (MCT 60 mg/kg, sc). The rats were orally treated with either SAA (0.3, 1, 3 mg·kg -1 ·d -1 ) or a positive control bosentan (30 mg·kg -1 ·d -1 ) for 4 weeks. Echocardiography and hemodynamic measurements were performed on d 28. Then the hearts and lungs were harvested, the organ indices and pulmonary artery wall thickness were calculated, and biochemical and histochemical analysis were conducted. The levels of apoptotic and signaling proteins in the lungs were measured using immunoblotting. Results: Treatment with SAA or bosentan effectively ameliorated MCT-induced pulmonary artery remodeling, pulmonary hemodynamic abnormalities and the subsequent increases of right ventricular systolic pressure (RVSP). Furthermore, the treatments significantly attenuated MCT-induced hypertrophic damage of myocardium, parenchymal injury and collagen deposition in the lungs. Moreover, the treatments attenuated MCT-induced apoptosis and fibrosis in the lungs. The treatments partially restored MCT-induced reductions of bone morphogenetic protein type II receptor (BMPRII) and phosphorylated Smad1/5 in the lungs. Conclusion: SAA ameliorates the pulmonary arterial remodeling in MCT-induced PAH rats most likely via activating the BMPRII-Smad pathway and inhibiting apoptosis. Thus, SAA may have therapeutic potential for the patients at high risk of PAH.

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“…DUSP4 is an inducible nuclear phosphatase whose substrates include all three of the MAPKs (ERK, JNK and p38) and it has been demonstrated to be important for cardiovascular function [16, 21-26]. Overexpression of DUSP4 in human endothelial cells enhances adhesion molecule expression and protects against apoptosis [22].…”

Section: Introductionmentioning

confidence: 99%

Modulation of p38 kinase by DUSP4 is important in regulating cardiovascular function under oxidative stress

Barajas-Espinosa

Basye

Angelos

2015

Free Radical Biology and Medicine

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Over-activation of p38 is implicated in many cardiovascular diseases (CVDs), including myocardial infarction, hypertrophy, heart failure, and ischemic heart disease. Numerous therapeutic interventions for CVDs have been directed towards the inhibition of the p38 mitogen-activated protein kinase activation that contributes to the detrimental effect after ischemia/reperfusion (I/R) injuries. However, the efficacy of these treatments is far from ideal as they lack specificity and are associated with high toxicity. Previously, we demonstrated that N-acetyl cysteine (NAC) pre-treatment up-regulates DUSP4 expression in endothelial cells, regulating p38 and ERK1/2 activities, thus providing a protective effect against oxidative stress. Here, endothelial cells under hypoxia/reoxygenation (H/R) insult and isolated heart I/R injury were used to investigate the role of DUSP4 on the modulation of the p38 pathway. In rat endothelial cells, DUSP4 is time-dependently degraded with H/R (0.25 ± 0.07 fold change of control after 2 h H/R). Its degradation is closely associated with hyper-phosphorylation of p38 (2.1 ± 0.36 fold change) and cell apoptosis, as indicated by the increase in cells immunopositive for cleaved caspase-3 (12.59% ± 3.38%) or TUNEL labeling (29.46% ± 3.75%). The inhibition of p38 kinase activity with 20 µM SB203580 during H/R prevents H/R-induced apoptosis, assessed via TUNEL (12.99% ± 1.89%). Conversely, DUSP4 gene silencing in endothelial cells augments their sensitivity to H/R-induced apoptosis (45.81% ± 5.23%). This sensitivity is diminished via the inhibition of p38 activity (total apoptotic cells drop to 17.47% ± 1.45%). Interestingly, DUSP4 gene silencing contributes to the increase in superoxide generation from cells. Isolated Langendorff-perfused mouse hearts were subjected to global I/R injury. DUSP4−/− hearts had significantly larger infarct size than WT. The increase in I/R-induced infarct in DUSP4−/− mice significantly correlates with reduced functional recovery (assessed by: RPP%, LVDP%, HR%, and dP/dtmax) as well as lower CF% and a higher initial LVEDP. From immunoblotting analysis, it is evident that p38 is significantly over-activated in DUSP4−/− mice after I/R injury. The activation of cleaved caspase-3 is seen in both WT and DUSP4−/− I/R hearts. Infusion of a p38 inhibitor prior to ischemia and during the reperfusion improves both WT and DUSP4−/− cardiac function. Therefore, the identification of p38 kinase modulation by DUSP4 provides a novel therapeutic target for oxidant-induced diseases, especially myocardial infarction.

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The Anti-Apoptotic and Cardioprotective Effects of Salvianolic Acid A on Rat Cardiomyocytes following Ischemia/Reperfusion by DUSP-Mediated Regulation of the ERK1/2/JNK Pathway

Cited by 48 publications

References 31 publications

Neuroprotective Effects of Crocin against Oxidative Stress Induced by Ischemia/Reperfusion Injury in Rat Retina

Neuroprotective Effects of Crocin against Oxidative Stress Induced by Ischemia/Reperfusion Injury in Rat Retina

Salvianolic acid A attenuates vascular remodeling in a pulmonary arterial hypertension rat model

Modulation of p38 kinase by DUSP4 is important in regulating cardiovascular function under oxidative stress

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