N-n-butyl Haloperidol Iodide Protects against Hypoxia/Reoxygenation Injury in Cardiac Microvascular Endothelial Cells by Regulating the ROS/MAPK/Egr-1 Pathway

Lu, Shishi; Zhang, Yanmei; Zhong, Shuming; Gao, Fenfei; Chen, Yicun; Li, Weiqiu; Zheng, Fangfang; Shi, Guo‐Ming

doi:10.3389/fphar.2016.00520

Cited by 18 publications

(26 citation statements)

References 27 publications

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“…CMECs were identified by flow cytometry using antibody against CD31 and VWF/Factor VIII, which are constitutively expressed on the surface of CMECs. Hypoxia was induced as before with some modifications . Briefly, CMECs were cultured in hypoxia solution in an air‐tight chamber saturated with pure N 2 at 37°C for 2 hours; the culture conditions were then returned to normal for 2 hours of reoxygenation.…”

Section: Methodsmentioning

confidence: 99%

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miR‐200a mediates protection of thymosin β‐4 in cardiac microvascular endothelial cells as a novel mechanism under hypoxia‐reoxygenation injury

Zhu

Liu

et al. 2019

J of Cellular Biochemistry

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Thymosin β‐4 (Tβ4) is a ubiquitous protein, which has been suggested to regulate multiple cell signal pathways and a variety of cellular functions. However, the role Tβ4 plays in the cardiac microvascular endothelial cells (CMECs) under myocardial ischemia/reperfusion injury is currently unknown. Here we investigated the effects of Tβ4 on hypoxia/reoxygenation (H/R) induced CMECs injury and its potential molecular mechanism. Cultured CMECs were positively identified by flow cytometry using antibody against CD31 and VWF/Factor VIII, which are constitutively expressed on the surface of CMECs. Then the reduced level of Tβ4 was detected in H/R‐CMECs by a real‐time quantitative polymerase chain reaction. To determine the effects of Tβ4 on H/R‐CMECs, we transfected the overexpression or silence vector of Tβ4 into CMECs under H/R condition. Our results indicated that H/R treatment could reduce proliferation, increased apoptosis, adhesion, and reactive oxygen species (ROS) production in CMECs, which were attenuated by Tβ4 overexpression or aggravated by Tβ4 silencing, implying Tβ4 is able to promote CMECs against H/R‐induced cell injury. Furthermore, the microRNA‐200a (miR‐200a) level was also increased by Tβ4 in H/R‐CMECs or reduced by Tβ4 small interfering RNA. To investigated the mechanism of protective effects of Tβ4 on CMECs injury, the miR‐200a inhibitor was transfected into H/R‐CMECs. The results indicated that inhibition of miR‐200a inversed the protection of Tβ4 on H/R‐CMECs, specifically including cell proliferation, cell adhesion, cell apoptosis, and ROS production, as well as nuclear factor erythroid 2‐related factor 2 (Nrf2) nuclear translocation. In conclusion, our results determined that Tβ4 attenuated H/R‐induced CMECs injury by miR‐200a‐Nrf2 signaling.

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Section: Methodsmentioning

confidence: 99%

“…Hypoxia was induced as before with some modifications. 17 Briefly, CMECs were cultured in hypoxia solution in an air-tight chamber saturated with pure N 2 at 37°C for 2 hours; the culture conditions were then returned to normal for 2 hours of reoxygenation.…”

Section: Cell Culture and Treatmentmentioning

confidence: 99%

miR‐200a mediates protection of thymosin β‐4 in cardiac microvascular endothelial cells as a novel mechanism under hypoxia‐reoxygenation injury

Zhu

Liu

et al. 2019

J of Cellular Biochemistry

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“…Numerous studies have shown that reactive oxygen species (ROS)-induced oxidative stress is key to myocardial I/R injury ( Murphy and Steenbergen, 2008 ; Radak et al, 2011 ; Minamino, 2012 ). Both Egr-1 and ROS are closely related to I/R injury, and our previous research has shown that the ROS/MAPK/Egr-1 signaling pathway is activated during hypoxia/reoxygenation (H/R) models of myocardial and cardiac microvascular endothelial cells (CMEC) ( Zhang et al, 2015 ; Lu S. et al, 2016 ). Bek’s group reported that over-expressed Egr-1 in proximal tubule epithelial cells downregulates expression of Cu/Zn-SOD and Mn-SOD, resulting in increased tissue ROS ( Bek et al, 2003 ).…”

Section: Introductionmentioning

confidence: 99%

N-n-Butyl Haloperidol Iodide, a Derivative of the Anti-psychotic Haloperidol, Antagonizes Hypoxia/Reoxygenation Injury by Inhibiting an Egr-1/ROS Positive Feedback Loop in H9c2 Cells

et al. 2018

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Early growth response-1 (Egr-1), a transcription factor which often underlies the molecular basis of myocardial ischemia/reperfusion (I/R) injury, and oxidative stress, is key to myocardial I/R injury. Silent information regulator of transcription 1(SIRT1) not only interacts with and is inhibited by Egr-1, but also downregulates reactive oxygen species (ROS) via the Forkhead box O1(FOXO1)/manganese superoxide dismutase (Mn-SOD) signaling pathway. N-n-butyl haloperidol iodide (F2), a new patented compound, protects the myocardium against myocardial I/R injury in various animal I/R models in vivo and various heart-derived cell hypoxia/reoxygenation (H/R) models in vitro. In addition, F2 can regulate the abnormal ROS/Egr-1 signaling pathway in cardiac microvascular endothelial cells (CMECs) and H9c2 cells after H/R. We studied whether there is an inverse Egr-1/ROS signaling pathway in H9c2 cells and whether the SIRT1/FOXO1/Mn-SOD signaling pathway mediates this. We verified a ROS/Egr-1 signaling loop in H9c2 cells during H/R and that F2 protects against myocardial H/R injury by affecting SIRT1-related signaling pathways. Knockdown of Egr-1, by siRNA interference, reduced ROS generation, and alleviated oxidative stress injury induced by H/R, as shown by upregulated mitochondrial membrane potential, increased glutathione peroxidase (GSH-px) and total SOD anti-oxidative enzyme activity, and downregulated MDA. Decreases in FOXO1 protein expression and Mn-SOD activity occurred after H/R, but could be blocked by Egr-1 siRNA. F2 treatment attenuated H/R-induced Egr-1 expression, ROS generation and other forms of oxidative stress injury such as MDA, and prevented H/R-induced decreases in FOXO1 and Mn-SOD activity. Nuclear co-localization between Egr-1 and SIRT1 was increased by H/R and decreased by either Egr-1 siRNA or F2. Therefore, our results suggest that Egr-1 inhibits the SIRT1/FOXO1/Mn-SOD antioxidant signaling pathway to increase ROS and perpetuate I/R injury. F2 inhibits induction of Egr-1 by H/R, thereby activating SIRT1/FOXO1/Mn-SOD antioxidant signaling and decreasing H/R-induced ROS, demonstrating an important mechanism by which F2 protects against myocardial H/R injury.

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“…Epigenetics refers to the modulation of gene expression via post-translational modification of protein complexes associated with DNA, without changing the DNA sequence (16,17). Among the several protein/histone modifications are acetylation, methylation, phosphorylation, ubiquitination, and sumoylation (17,18).…”

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confidence: 99%

Targeting histone methyltransferase enhancer of zeste homolog‐2 inhibits renal epithelial‐mesenchymal transition and attenuates renal fibrosis

et al. 2018

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Enhancer of zeste homolog-2 (EZH2) is a methyltransferase that induces histone H3 lysine 27 trimethylation (H3K27me3) and functions as an oncogenic factor in many cancer types. Its role in renal epithelial-mesenchymal transition (EMT) remains unknown. In this study, we found that EZH2 and H3K27me3 were highly expressed in mouse kidney with unilateral ureteral obstruction and cultured mouse kidney proximal tubular (TKPT) cells undergoing EMT. Inhibition of EZH2 with 3-deazaneplanocin A (3-DZNeP) attenuated renal fibrosis, which was associated with preserving E-cadherin expression and inhibiting Vimentin up-regulation in the obstructed kidney. Treatment with 3-DZNeP or transfection of EZH2 siRNA also inhibited TGF-β1-induced EMT of TKPT cells. Injury to the kidney or cultured TKPT cells resulted in up-regulation of Snail-l family transcriptional repressor (Snail)-1 and Twist family basic helix-loop-helix (BHLH) transcription factor (Twist)-1, which are 2 transcription factors, and down-regulation of phosphatase and tensin homolog, a protein tyrosine phosphatase associated with inhibition of PI3K-protein kinase B (AKT) signaling; EZH2 inhibition or silencing reversed all those responses. 3-DZNeP was also effective in suppressing epithelial arrest at the G/M phase and dephosphorylating AKT and β-catenin in vivo and in vitro. These data indicate that EZH2 activation contributes to renal EMT and fibrosis through activation of multiple signaling pathways and suggest that EZH2 has potential as a therapeutic target for treatment of renal fibrosis.-Zhou, X., Xiong, C., Tolbert, E., Zhao, T. C., Bayliss, G., Zhuang, S. Targeting histone methyltransferase enhancer of zeste homolog-2 inhibits renal epithelial-mesenchymal transition and attenuates renal fibrosis.

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N-n-butyl Haloperidol Iodide Protects against Hypoxia/Reoxygenation Injury in Cardiac Microvascular Endothelial Cells by Regulating the ROS/MAPK/Egr-1 Pathway

Cited by 18 publications

References 27 publications

miR‐200a mediates protection of thymosin β‐4 in cardiac microvascular endothelial cells as a novel mechanism under hypoxia‐reoxygenation injury

miR‐200a mediates protection of thymosin β‐4 in cardiac microvascular endothelial cells as a novel mechanism under hypoxia‐reoxygenation injury

N-n-Butyl Haloperidol Iodide, a Derivative of the Anti-psychotic Haloperidol, Antagonizes Hypoxia/Reoxygenation Injury by Inhibiting an Egr-1/ROS Positive Feedback Loop in H9c2 Cells

Targeting histone methyltransferase enhancer of zeste homolog‐2 inhibits renal epithelial‐mesenchymal transition and attenuates renal fibrosis

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