Dataset Information

Protective effect of butin against ischemia/reperfusion-induced myocardial injury in diabetic mice: involvement of the AMPK/GSK-3?/Nrf2 signaling pathway.

ABSTRACT: Hyperglycemia-induced reactive oxygen species (ROS) generation contributes to development of diabetic cardiomyopathy (DCM). This study was designed to determine the effect of an antioxidant butin (BUT) on ischemia/reperfusion-induced myocardial injury in diabetic mice. Myocardial ischemia/reperfusion (MI/R) was induced in C57/BL6J diabetes mice. Infarct size and cardiac function were detected. For in vitro study, H9c2 cells were used. To clarify the mechanisms, proteases inhibitors or siRNA were used. Proteins levels were investigated by Western blotting. In diabetes MI/R model, BUT significantly alleviated myocardial infarction and improved heart function, together with prevented diabetes-induced cardiac oxidative damage. The expression of Nrf2, AMPK, AKT and GSK-3? were significantly increased by BUT. Furthermore, in cultured H9c2 cardiac cells silencing Nrf2 gene with its siRNA abolished the BUT's prevention of I/R-induced myocardial injury. Inhibition of AMPK and AKT signaling by relative inhibitor or specific siRNA decreased the level of BUT-induced Nrf2 expression, and diminished the protective effects of BUT. The interplay relationship between GSK-3? and Nrf2 was also verified with relative overexpression and inhibitors. Our findings indicated that BUT protected against I/R-induced ROS-mediated apoptosis by upregulating the AMPK/Akt/GSK-3? pathway, which further activated Nrf2-regulated antioxidant enzymes in diabetic cardiomyocytes exposed to I/R.

SUBMITTER: Duan J

PROVIDER: S-EPMC5269748 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Protective effect of butin against ischemia/reperfusion-induced myocardial injury in diabetic mice: involvement of the AMPK/GSK-3β/Nrf2 signaling pathway.

Duan Jialin J Guan Yue Y Mu Fei F Guo Chao C Zhang Enhu E Yin Ying Y Wei Guo G Zhu Yanrong Y Cui Jia J Cao Jinyi J Weng Yan Y Wang Yanhua Y Xi Miaomiao M Wen Aidong A

Scientific reports 20170127

Hyperglycemia-induced reactive oxygen species (ROS) generation contributes to development of diabetic cardiomyopathy (DCM). This study was designed to determine the effect of an antioxidant butin (BUT) on ischemia/reperfusion-induced myocardial injury in diabetic mice. Myocardial ischemia/reperfusion (MI/R) was induced in C57/BL6J diabetes mice. Infarct size and cardiac function were detected. For in vitro study, H9c2 cells were used. To clarify the mechanisms, proteases inhibitors or siRNA were ...[more]

PMID: 28128361

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Project description:RationaleEndothelial progenitor cells (EPCs) respond to stromal cell-derived factor 1 (SDF-1) through chemokine receptors CXCR7 and CXCR4. Whether SDF-1 receptors involves in diabetes mellitus-induced EPCs dysfunction remains unknown.ObjectiveTo determine the role of SDF-1 receptors in diabetic EPCs dysfunction.Methods and resultsCXCR7 expression, but not CXCR4 was reduced in EPCs from db/db mice, which coincided with impaired tube formation. Knockdown of CXCR7 impaired tube formation of EPCs from normal mice, whereas upregulation of CXCR7 rescued angiogenic function of EPCs from db/db mice. In normal EPCs treated with oxidized low-density lipoprotein or high glucose also reduced CXCR7 expression, impaired tube formation, and increased oxidative stress and apoptosis. The damaging effects of oxidized low-density lipoprotein or high glucose were markedly reduced by SDF-1 pretreatment in EPCs transduced with CXCR7 lentivirus but not in EPCs transduced with control lentivirus. Most importantly, EPCs transduced with CXCR7 lentivirus were superior to EPCs transduced with control lentivirus for therapy of ischemic limbs in db/db mice. Mechanistic studies demonstrated that oxidized low-density lipoprotein or high glucose inhibited protein kinase B and glycogen synthase kinase-3β phosphorylation, nuclear export of Fyn and nuclear localization of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), blunting Nrf2 downstream target genes heme oxygenase-1, NAD(P)H dehydrogenase (quinone 1) and catalase, and inducing an increase in EPC oxidative stress. This destructive cascade was blocked by SDF-1 treatment in EPCs transduced with CXCR7 lentivirus. Furthermore, inhibition of phosphatidylinositol 3-kinase/protein kinase B prevented SDF-1/CXCR7-mediated Nrf2 activation and blocked angiogenic repair. Moreover, Nrf2 knockdown almost completely abolished the protective effects of SDF-1/CXCR7 on EPC function in vitro and in vivo.ConclusionsElevated expression of CXCR7 enhances EPC resistance to diabetes mellitus-induced oxidative damage and improves therapeutic efficacy of EPCs in treating diabetic limb ischemia. The benefits of CXCR7 are mediated predominantly by a protein kinase B/glycogen synthase kinase-3β/Fyn pathway via increased activity of Nrf2.

Project description:Background Myocardial necrosis caused by myocardial ischemia-reperfusion (MI/R) in diabetic patients is prominently aggravated and can cause oxidative stress. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensing transcription factor that protects against myocardial ischemia/reperfusion injury (MIRI). However, the mechanism of action of Nrf2 in resveratrol-pretreated cardiomyocytes is complex. We assumed that adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/p38 mitogen-activated protein kinases (p38)/Nrf2 might be involved in resveratrol alleviating MIRI in diabetic rats as an endogenous protective mechanism. Methods A total of 50 type 2 diabetes mellitus (T2DM) rat models were randomly divided into 5 groups (n=10 in each group): sham group; MI/R group; AMPK inhibitor compound C + myocardial ischemia-reperfusion (C + MI/R) group; resveratrol + myocardial ischemia-reperfusion (RSV + MI/R) group; and resveratrol + AMPK inhibitor compound C + myocardium ischemia-reperfusion group (RSV + C + MI/R) group. Rats were fed a high fat diet, and the T2DM models were established by intraperitoneal injection of 1% streptozotocin (STZ). The MIRI models were established by ligating the left anterior descending coronary artery for 30 minutes followed by reperfusion for 120 minutes. The size of myocardial infarction was measured. Serum samples were collected to measure the concentrations of creatine kinase-MB (CK-MB). The levels of lactate dehydrogenase (LDH), glutathione (GSH), and superoxide dismutase (SOD) in myocardial tissues were determined. Immunofluorescence analysis of translocase of outer mitochondrial membrane 20 (TOMM20) was performed to observe the pathological changes in myocardial tissues. The protein expressions of AMPK, p-AMPK, p38, p-p38, Nrf2, and heme oxygenase 1 (HO-1) were determined by western blotting. Results Compared with the sham group, the expressions of AMPK, p38, Nrf2, and HO-1 in the myocardium were significantly increased in the MI/R group. Compared with the MI/R group, the RSV + MI/R group had a significantly lower oxidative stress level, milder myocardial injury, increased expressions of AMPK, Nrf2, and HO-1, and lower expression of p38. The protein expressions of Nrf2 and HO-1 were partially inhibited in the RSV + C + MI/R group. Conclusions Resveratrol can inhibit oxidative stress and alleviate MIRI by activating the AMPK/p38/Nrf2 signaling pathway. Meanwhile, AMPK/p38/Nrf2 is also an endogenous antioxidant stress pathway that protects against stress.

Dataset Information

Protective effect of butin against ischemia/reperfusion-induced myocardial injury in diabetic mice: involvement of the AMPK/GSK-3?/Nrf2 signaling pathway.

Publications

Protective effect of butin against ischemia/reperfusion-induced myocardial injury in diabetic mice: involvement of the AMPK/GSK-3β/Nrf2 signaling pathway.

Similar Datasets

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