Involvement of Nrf2 in myocardial ischemia and reperfusion injury

Shen, Yiming; Liu, Xiaojuan; Shi, Jiahai; Xiang, Wu

doi:10.1016/j.ijbiomac.2018.11.190

Cited by 192 publications

(133 citation statements)

References 123 publications

Supporting

Mentioning

113

Contrasting

Unclassified

Order By: Relevance

“…The lack of Nrf2/ARE gene up-regulation in our model of IR is in line with the data recently published by our group showing that in peripheral blood mononuclear cells derived from patients with peripheral artery disease subjected to one cycle of IR, there was no up-regulation of Nrf2/ARE gene expression [14]. At variance with our results, previous studies have shown a protective role of the Nrf2/ARE pathway in animal models of myocardial ischemia and reperfusion injury [36,37]. It is likely that these differences are related to the different experimental conditions.…”

Section: Discussionsupporting

confidence: 92%

Ezetimibe Prevents Ischemia/Reperfusion-Induced Oxidative Stress and Up-Regulates Nrf2/ARE and UPR Signaling Pathways

et al. 2020

View full text Add to dashboard Cite

Background: While reperfusion is crucial for survival after an episode of ischemia, it also causes oxidative stress. Nuclear factor-E2-related factor 2 (Nrf2) and unfolded protein response (UPR) are protective against oxidative stress and endoplasmic reticulum (ER) stress. Ezetimibe, a cholesterol absorption inhibitor, has been shown to activate the AMP-activated protein kinase (AMPK)/Nrf2 pathway. In this study we evaluated whether Ezetimibe affects oxidative stress and Nrf2 and UPR gene expression in cellular models of ischemia-reperfusion (IR). Methods: Cultured cells were subjected to simulated IR with or without Ezetimibe. Results: IR significantly increased reactive oxygen species (ROS) production and the percentage of apoptotic cells without the up-regulation of Nrf2, of the related antioxidant response element (ARE) gene expression or of the pro-survival UPR activating transcription factor 6 (ATF6) gene, whereas it significantly increased the pro-apoptotic CCAAT-enhancer-binding protein homologous protein (CHOP). Ezetimibe significantly decreased the cellular ROS formation and apoptosis induced by IR. These effects were paralleled by the up-regulation of Nrf2/ARE and ATF6 gene expression and by a down-regulation of CHOP. We also found that Nrf2 activation was dependent on AMPK, since Compound C, a pan inhibitor of p-AMPK, blunted the activation of Nrf2. Conclusions: Ezetimibe counteracts IR-induced oxidative stress and induces Nrf2 and UPR pathway activation.

show abstract

Section: Discussionsupporting

confidence: 92%

Ezetimibe Prevents Ischemia/Reperfusion-Induced Oxidative Stress and Up-Regulates Nrf2/ARE and UPR Signaling Pathways

et al. 2020

View full text Add to dashboard Cite

show abstract

“…It is well accepted that the phosphorylation of Nrf2 by protein kinases, such as PKC and PI3K, promotes the nuclear translocation of Nrf2 by dissociating from Keap1. 14 In the present study, it was also demonstrated that SA enhanced the phosphorylation of Nfr2, via the PKC or PI3K pathway. These findings may give a new insight into how SA induces the nuclear translocation of Nrf2.…”

Section: Dovepresssupporting

confidence: 69%

<p>Sappanone A Protects Against Myocardial Ischemia Reperfusion Injury by Modulation of Nrf2</p>

Shi

Gao

et al. 2020

DDDT

View full text Add to dashboard Cite

Background: Oxidative stress is a major contributor to the onset and development of myocardial ischemia reperfusion injury (MIRI). Sappanone A (SA), a homoisoflavanone extracted from the heartwood of Caesalpinia sappan L., has been demonstrated to possess powerful antioxidant activity. Therefore, this study aimed to determine the protective effect of SA on MIRI and investigate its underlying mechanism. Methods: The rat hearts were isolated and underwent 30-min ischemia, followed by 120min reperfusion to establish the MIRI model, using the Langendorff method. SA was administrated intraperitoneally into rats 1 h prior to heart isolation. The myocardial infarct size and apoptosis were measured by TTC and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Myocardial enzyme activity, MDA content and the activities of SOD and GSH-Px were detected by colorimetric spectrophotometric method. Reactive oxygen species (ROS) level was detected by DCFH-DA probe. The change in Keap1/Nrf2 signaling pathway was evaluated by Western blotting. Results: SA reduced myocardial infarct size and the release of CK-MB and LDH in a dosedependent manner. Moreover, SA improved the recovery of cardiac function, inhibited MIRI-induced apoptosis, repressed the production of ROS and MDA, and enhanced the activities of SOD and GSH-Px. Mechanistically, SA downregulated Keap1, induced Nrf2 nuclear accumulation, and enhanced Nrf2 transcriptional activity, subsequently resulting in an increase in the expression of the Nrf2 target genes heme oxygenase-1 and NAD(P)H quinone dehydrogenase 1. Moreover, SA enhanced the phosphorylation of Nfr2, but the enhancement in Nfr2 phosphorylation was abrogated by PKC or PI3K inhibitor. Conclusion: Collectively, it was demonstrated that SA prevents MIRI via coordinating the cellular antioxidant defenses and maintaining the redox balance, by modulation of Nrf2 via the PKC or PI3K pathway. Therefore, SA was a potential therapeutic drug for treating MIRI.

show abstract

“…Nrf2 is widely present in oxygen-consuming organs, such as the muscle tissue, heart, blood vessels, liver, kidney, and brain, and it is an important regulator of oxidative stress. Nrf2 activation can induce the synthesis of antioxidant enzymes, binomial detoxifying enzymes, and antiinflammatory factors [33]. Under normal physiological 7 Oxidative Medicine and Cellular Longevity conditions, Keap1 chelates with Nrf2 in the cytosol and thus prevents Nrf2 transcription.…”

Section: Discussionmentioning

confidence: 99%

Astaxanthin Protects Ochratoxin A-Induced Oxidative Stress and Apoptosis in the Heart via the Nrf2 Pathway

Cui

et al. 2020

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

This study assessed the protective mechanism of astaxanthin (ASX) against ochratoxin A- (OTA-) induced cardiac injury in mice. Four groups of mice were established: control group (0.1 mL olive oil+0.1 mL NaHCO2), OTA group (0.1 mL OTA 5 mg/kg body weight), ASX group (0.1 mL ASX 100 mg/kg body weight), and ASX + OTA group (0.1 mL ASX 100 mg/kg body weight, 2 h later, 0.1 mL OTA 5 mg/kg body weight). The test period lasted for 27 days (7 days of dosing, 2 days of rest). Electrocardiogram, body weight, heart weight, tissue pathology, oxidative markers (malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH)), biochemical markers (creatine kinase (CK), creatine kinase isoenzyme (CK-MB), and lactate dehydrogenase (LDH)), electron microscopy, TUNEL, and Western blot tests were used to examine the effects of OTA on myocardial injury and ASX detoxification. The results showed that OTA exposure significantly decreased both body weight and heart weight. OTA induced a decrease in heart rate in mice and decreased tissue concentrations of SOD, CAT, and GSH, while increasing serum concentrations of cardiac enzymes (CK, CK-MB, and LDH) and tissue MDA. ASX improved heart rate, cardiac enzymes, and antioxidant levels in mice. The results of tissue pathology and TUNEL assay showed that ASX protects against OTA-induced myocardial injury. In addition, Western blot results showed that the OTA group upregulated Keap1, Bax, Caspase3, and Caspase9, while it downregulated Nrf2, HO-1, and Bcl-2 protein expression. ASX played a protective role by changing the expression of Keap1, Nrf2, HO-1, Bax, Bcl-2, Caspase3, and Caspase9 proteins. These results indicate that the protective mechanism of ASX on the myocardium works through the Keap1-Nrf2 signaling pathway and mitochondria-mediated apoptosis pathway. This study provides a molecular rationale for the mechanism underlying OTA-induced myocardial injury and the protective effect of ASX on the myocardium.

show abstract

Involvement of Nrf2 in myocardial ischemia and reperfusion injury

Cited by 192 publications

References 123 publications

Ezetimibe Prevents Ischemia/Reperfusion-Induced Oxidative Stress and Up-Regulates Nrf2/ARE and UPR Signaling Pathways

Ezetimibe Prevents Ischemia/Reperfusion-Induced Oxidative Stress and Up-Regulates Nrf2/ARE and UPR Signaling Pathways

<p>Sappanone A Protects Against Myocardial Ischemia Reperfusion Injury by Modulation of Nrf2</p>

Astaxanthin Protects Ochratoxin A-Induced Oxidative Stress and Apoptosis in the Heart via the Nrf2 Pathway

Contact Info

Product

Resources

About