Heme oxygenase 1 induction protects myocardiac cells against hypoxia/reoxygenation-induced apoptosis

Li, C.; Zhang, C.; Wang, T.; Xuan, Jichang; Su, C.; Wang, Y.

doi:10.1007/s00059-016-4424-6

Cited by 18 publications

(11 citation statements)

References 34 publications

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“…JNK is a member of the MAPK family, which modulates various cellular functions, including proliferation, differentiation, and cell apoptosis [30]. Research on H/R or I/R models in the myocardium [31], renal cells [32], and the brain [33] showed that activated JNK mediates injury and that inhibition of p-JNK expression can reduce H/R- or I/R-induced apoptosis, death, or necrosis. Previous studies in our laboratory also indicated that the inhibition of JNK activation can improve the survival of cardiac microvascular endothelial cells [5], which were supported by the results of Li et al [31] and Sun et al [34].…”

Section: Discussionmentioning

confidence: 99%

N-n-Butyl Haloperidol Iodide Ameliorates Oxidative Stress in Mitochondria Induced by Hypoxia/Reoxygenation through the Mitochondrial c-Jun N-Terminal Kinase/Sab/Src/Reactive Oxygen Species Pathway in H9c2 Cells

Chu

Zhang

Zhong

et al. 2019

Oxidative Medicine and Cellular Longevity

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Both c-Jun N-terminal kinase (JNK) and reactive oxygen species (ROS) play important roles in myocardial ischemia/reperfusion (I/R) injury. Our previous studies suggest that N-n-butyl haloperidol iodide (F2) exerts cardioprotection by reducing ROS production and JNK activation caused by I/R. In this study, we hypothesized that there is a JNK/Sab/Src/ROS pathway in the mitochondria in H9c2 cells following hypoxia/reoxygenation (H/R) that induces oxidative stress in the mitochondria and that F2 exerts mitochondrial protective effects during H/R injury by modulating this pathway. The results showed that H/R induced higher-level ROS in the cytoplasm on the one hand and JNK activation and translocation to the mitochondria by colocalization with Sab on the other. Moreover, H/R resulted in mitochondrial Src dephosphorylation, and subsequently, oxidative stress evidenced by the increase in ROS generation and oxidized cardiolipin in the mitochondrial membranes and by the decrease in mitochondrial superoxide dismutase activity and membrane potential. Furthermore, treatment with a JNK inhibitor or Sab small interfering RNA inhibited the mitochondrial translocation of p-JNK, decreased colocalization of p-JNK and Sab on the mitochondria, and reduced Src dephosphorylation and mitochondrial oxidative stress during H/R. In addition, Src dephosphorylation by inhibitor PP2 increased mitochondrial ROS production. F2, like inhibitors of the JNK/Sab/Src/ROS pathway, downregulated the H/R-induced mitochondrial translocation of p-JNK and the colocalization of p-JNK and Sab on the mitochondria, increased Src phosphorylation, and alleviated the above-mentioned mitochondrial oxidative stress. In conclusion, F2 could ameliorate H/R-associated oxidative stress in mitochondria in H9c2 cells through the mitochondrial JNK/Sab/Src/ROS pathway.

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Section: Discussionmentioning

confidence: 99%

N-n-Butyl Haloperidol Iodide Ameliorates Oxidative Stress in Mitochondria Induced by Hypoxia/Reoxygenation through the Mitochondrial c-Jun N-Terminal Kinase/Sab/Src/Reactive Oxygen Species Pathway in H9c2 Cells

Chu

Zhang

Zhong

et al. 2019

Oxidative Medicine and Cellular Longevity

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“…Apoptotic cells were measured by Hoechst 33342 staining under a fluorescence microscope. Briefly, the cells were seeded in 6-well plates, stained with Hoechst 33342 for 5 min in the dark, and washed with PBS three times [ 34 ]. Then, the cells were observed using a fluorescence microscopy (IX73, Olympus, Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

High Glucose-Induced Cardiomyocyte Death May Be Linked to Unbalanced Branched-Chain Amino Acids and Energy Metabolism

et al. 2018

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High glucose-induced cardiomyocyte death is a common symptom in advanced-stage diabetic patients, while its metabolic mechanism is still poorly understood. The aim of this study was to explore metabolic changes in high glucose-induced cardiomyocytes and the heart of streptozotocin-induced diabetic rats by 1H-NMR-based metabolomics. We found that high glucose can promote cardiomyocyte death both in vitro and in vivo studies. Metabolomic results show that several metabolites exhibited inconsistent variations in vitro and in vivo. However, we also identified a series of common metabolic changes, including increases in branched-chain amino acids (BCAAs: leucine, isoleucine and valine) as well as decreases in aspartate and creatine under high glucose condition. Moreover, a reduced energy metabolism could also be a common metabolic characteristic, as indicated by decreases in ATP in vitro as well as AMP, fumarate and succinate in vivo. Therefore, this study reveals that a decrease in energy metabolism and an increase in BCAAs metabolism could be implicated in high glucose-induced cardiomyocyte death.

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“…Pro-BDNF shows high-affinity binding to sortilin and performs its biological functions by acting on its receptors: p75 NTR and sortilin [ 45 ]. Some studies have indicated that the JNK pathway contributes to the growth-inhibitory effect and apoptosis of ECs and that inhibition of JNK activation protects cardiomyocytes from I/R injury [ 46 – 49 ]. Pro-NGF/p75NTR/sortilin signaling increases JNK signaling [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

“…Diabetic nephropathy is a serious microvascular complication of DM; H/R promoted oxidative stress in NRK-52E cells exposed to HG accompanied by increased levels of Nrf2 and HO-1 protein expression [ 32 , 46 ]. High glucose has also been proved to increase the permeability of cardiac microvascular endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Pro‐BDNF Contributes to Hypoxia/Reoxygenation Injury in Myocardial Microvascular Endothelial Cells: Roles of Receptors p75^NTR and Sortilin and Activation of JNK and Caspase 3

Liu

2018

Oxidative Medicine and Cellular Longevity

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The aim of this study was to identify the role of the precursor of the brain-derived neurotrophic factor (pro-BDNF) in myocardial hypoxia/reoxygenation injury (H/R) and to address the underlying mechanisms. For this purpose, myocardial microvascular endothelial cells (MMECs) exposed to a high concentration of glucose (30 mM) for 48 h were subjected to 4 h of hypoxia followed by 2 h of reoxygenation. Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) staining and flow-cytometric analysis were performed to detect apoptosis. Cell scratch and capillary-like-structure formation assays were employed to evaluate cell function. The levels of apoptosis-related proteins were evaluated by Western blotting and immunofluorescence assays. Our results showed that H/R resulted in MMEC injury, as indicated by significant increases in TUNEL-positive cell numbers and a reduction in MMEC migration and in capillary-like-structure formation coupled with increased pro-BDNF protein expression. In addition, overexpression of pro-BDNF in MMECs via a viral vector led to increased pro-BDNF expression, and this upregulation induced apoptosis. Mechanistic experiments revealed that H/R did not influence BDNF, JNK, and caspase 3 expression, but upregulated pro-BDNF, p75NTR, sortilin, phospho-JNK, and cleaved caspase 3 protein levels. In contrast, neutralization of endogenous pro-BDNF with an antibody significantly attenuated H/R-induced upregulation of pro-BDNF, p75NTR, sortilin, p-JNK, and cleaved caspase 3 protein levels, indicating that p75NTR-sortilin signaling and activation of JNK and caspase 3 may be involved in these effects. In conclusion, H/R-induced injury may be mediated by pro-BDNF, at least in part through the regulation of p75NTR-sortilin signaling and activation of JNK and caspase 3.

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Heme oxygenase 1 induction protects myocardiac cells against hypoxia/reoxygenation-induced apoptosis

Abstract: In summary, our results suggest that HO-1 can decrease H/R-induced myocardiac cell apoptosis; the mechanism may be related to the activation of the Akt signaling pathway and, furthermore, to the inhibition of the JNK/c-Jun/caspase-3 signaling pathway.

Cited by 18 publications

References 34 publications

N-n-Butyl Haloperidol Iodide Ameliorates Oxidative Stress in Mitochondria Induced by Hypoxia/Reoxygenation through the Mitochondrial c-Jun N-Terminal Kinase/Sab/Src/Reactive Oxygen Species Pathway in H9c2 Cells

N-n-Butyl Haloperidol Iodide Ameliorates Oxidative Stress in Mitochondria Induced by Hypoxia/Reoxygenation through the Mitochondrial c-Jun N-Terminal Kinase/Sab/Src/Reactive Oxygen Species Pathway in H9c2 Cells

High Glucose-Induced Cardiomyocyte Death May Be Linked to Unbalanced Branched-Chain Amino Acids and Energy Metabolism

Pro‐BDNF Contributes to Hypoxia/Reoxygenation Injury in Myocardial Microvascular Endothelial Cells: Roles of Receptors p75^NTR and Sortilin and Activation of JNK and Caspase 3

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Heme oxygenase 1 induction protects myocardiac cells against hypoxia/reoxygenation-induced apoptosis

Abstract: In summary, our results suggest that HO-1 can decrease H/R-induced myocardiac cell apoptosis; the mechanism may be related to the activation of the Akt signaling pathway and, furthermore, to the inhibition of the JNK/c-Jun/caspase-3 signaling pathway.

Cited by 18 publications

References 34 publications

N-n-Butyl Haloperidol Iodide Ameliorates Oxidative Stress in Mitochondria Induced by Hypoxia/Reoxygenation through the Mitochondrial c-Jun N-Terminal Kinase/Sab/Src/Reactive Oxygen Species Pathway in H9c2 Cells

N-n-Butyl Haloperidol Iodide Ameliorates Oxidative Stress in Mitochondria Induced by Hypoxia/Reoxygenation through the Mitochondrial c-Jun N-Terminal Kinase/Sab/Src/Reactive Oxygen Species Pathway in H9c2 Cells

High Glucose-Induced Cardiomyocyte Death May Be Linked to Unbalanced Branched-Chain Amino Acids and Energy Metabolism

Pro‐BDNF Contributes to Hypoxia/Reoxygenation Injury in Myocardial Microvascular Endothelial Cells: Roles of Receptors p75NTR and Sortilin and Activation of JNK and Caspase 3

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Pro‐BDNF Contributes to Hypoxia/Reoxygenation Injury in Myocardial Microvascular Endothelial Cells: Roles of Receptors p75^NTR and Sortilin and Activation of JNK and Caspase 3