Hemeoxygenase-1 Mediates an Adaptive Response to Spermidine-Induced Cell Death in Human Endothelial Cells

Yang, Hana; Lee, Seung Eun; Kim, Gun Dong; Park, Hye Rim; Park, Yong Seek

doi:10.1155/2013/238734

Cited by 14 publications

(7 citation statements)

References 40 publications

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“…It is well known that activation of PI3K/AKT signaling functions as a cytoprotective mechanism against oxidative stress (Mo et al 2012, Ryu et al 2014, Yang et al 2013. In this sense, our results demonstrated that, in addition to stimulating Hmox1 gene expression, treatment of Y1 cells with either ACTH or 8Br-cAMP also leads to an increase in Akt phosphorylation levels.…”

Section: Discussionsupporting

confidence: 72%

Role of CREB on heme oxygenase-1 induction in adrenal cells: involvement of the PI3K pathway

Astort

Repetto

Rocha-Viegas

et al. 2016

Journal of Molecular Endocrinology

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In addition to the well-known function of ACTH as the main regulator of adrenal steroidogenesis, we have previously demonstrated its effect on the transcriptional stimulation of HO-1 expression, a component of the cellular antioxidant defense system. In agreement, we hereby demonstrate that, in adrenocortical Y1 cells, HO-1 induction correlates with a significant prevention of the generation of reactive oxygen species induced by H 2 O 2 /Fe 2+ . ACTH/cAMP-dependent activation of redox-imbalanced related factors such as NRF2 or NFκB and the participation of MAPKs in this mechanism was, however, discarded based on results with specific inhibitors and reporter plasmids. We suggest the involvement of CREB in HO-1 induction by ACTH/cAMP, as transfection of cells with a dominant-negative isoform of CREB (DN-CREB-M1) decreased, while overexpression of CREB increased HO-1 protein levels. Sequence screening of the murine HO-1 promoter revealed CRE-like sites located at −146 and −37 of the transcription start site and ChIP studies indicated that this region recruits phosphorylated CREB (pCREB) upon cAMP stimulation in Y1 cells. In agreement, H89 (PKA inhibitor) or cotransfection with DN-CREB-M1 prevented the 8Br-cAMP-dependent increase in luciferase activity in cells transfected with pHO-1[−295/+74].LUC. ACTH and cAMP treatment induced the activation of the PI3K/Akt signaling pathway in a PKA-independent mechanism. Inhibition of this pathway prevented the cAMP-dependent increase in HO-1 protein levels and luciferase activity in cells transfected with pHO-1[−295/+74].LUC. Finally, here we show a crosstalk between the cAMP/PKA and PI3K pathways that affects the binding of p-CREB to its cognate element in the murine promoter of the Hmox1 gene. CREB mediates adrenal HO-1 induction by cAMPf astort, e m repetto and others (Gallo-Payet 2016). In turn, stimulation of PKA activity is involved in the phosphorylation and activation of several transcription factors engaged in the transcriptional stimulation of steroidogenic-related genes. Among them, the cAMP response element binding protein (CREB), the GATA-4 binding protein, the steroidogenic factor 1 (SF1) and the CAAT enhancer binding protein (C/EBP) could be included (Manna et al. 2003a,b, Stocco et al. 2005.Glucocorticoid synthesis in the adrenal cortex is a multistep process where mitochondrial and microsomal cytochrome P450 enzymes, mixed function oxidases, catalyze the hydroxylation of steroids and the reduction of O 2 to water. Even under physiological conditions, ACTHstimulated steroidogenesis generates oxidative stress, as incomplete reduction in O 2 leads to the production of reactive oxygen species (ROS), lipoperoxides and other oxygenated species (Hanukoglu 2006, Prasad et al. 2014. To cope with the potentially damaging effects associated with oxidative stress, adrenal cells activate several antioxidant mechanisms (Chinn et al. 2002, Hanukoglu 2006, Battista et al. 2009). Among them, we have previously shown that the ACTH-dependent induction of heme oxygenase...

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Section: Discussionsupporting

confidence: 72%

Role of CREB on heme oxygenase-1 induction in adrenal cells: involvement of the PI3K pathway

Astort

Repetto

Rocha-Viegas

et al. 2016

Journal of Molecular Endocrinology

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“…HO originally functions as a rate-limiting enzyme in heme degradation, yielding carbon monoxide (CO), iron, and biliverdin as the end products. HO-1 and HO-2 are isoforms of HO in mammals [1]. The HO-2 isoform is constitutively expressed; however, HO-1 is an inducible one.…”

Section: Introductionmentioning

confidence: 99%

Heme oxygenase (HO)-1 induction prevents Endoplasmic Reticulum stress-mediated endothelial cell death and impaired angiogenic capacity

Maamoun

Zachariah

McVey

et al. 2017

Biochemical Pharmacology

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Most of diabetic cardiovascular complications are attributed to endothelial dysfunction and impaired angiogenesis. Endoplasmic Reticulum (ER) and oxidative stresses were shown to play a pivotal role in the development of endothelial dysfunction in diabetes.Hemeoxygenase-1 (HO-1) was shown to protect against oxidative stress in diabetes; however, its role in alleviating ER stress-induced endothelial dysfunction remains not fully elucidated. We aim here to test the protective role of HO-1 against high glucose-mediated ER stress and endothelial dysfunction and understand the underlying mechanisms with special emphasis on oxidative stress, inflammation and cell death. Altogether, we show here the critical role of ER stress-mediated cell death in diabetesinduced endothelial dysfunction and impaired angiogenesis and underscore the role of HO-1 induction as a key therapeutic modulator for ER stress response in ischemic disorders and diabetes. Our results also highlight the complex interplay between ER stress response and oxidative stress.

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“…By exploring the inner connection of these metabolic pathways, 26 metabolic pathways associated with AKT pathways are found. AKT is activated by a number of receptor tyrosine kinases following the binding of growth factors or hormones such as PDGF and insulin, working as an important mediator of the 3-phosphoinositide-dependent kinase (PI3K) pathway [30][31][32][33]. Activated AKT can increase the expression of many pro-proliferative genes such as Bcl-2, decrease pro-apoptotic genes (Kv channels), and then lead to PAH [34].…”

Section: Discussionmentioning

confidence: 99%

Metabolomics-based mechanism exploration of pulmonary arterial hypertension pathogenesis: novel lessons from explanted human lungs

et al. 2022

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Background: Metabolic pathways have been shown to participate in the pathogenesis of pulmonary arterial hypertension (PAH). We investigated the metabolic pro le shifts to reveal molecular mechanisms underlying PAH.Methods: Explanted human lung tissues from 18 PAH patients were collected. The lung tissues far from the tumor from 16 lung cancer patients were taken as controls. Lung tissues were analyzed by LC-MS/MS based non-target metabolomics method. Pathway analysis was performed with KEGG database and MetaboAnalyst 5.0. Statistical analysis including partial least squares discriminant analysis (PLS-DA), Student's t-test, Pearson's correlation, Chi-square test and Fisher's exact probability test were used. COX survival analysis model was applied to evaluate the predictive value of metabolites on prognosis. Protein expression levels were detected by Western blotting in human PAH lung tissues, rat monocrotaline-PAH lungs and hypoxia exposed human pulmonary artery smooth muscle cells (HPASMCs) to study the molecular mechanisms.Results: Signi cant differences in metabolites and metabolic pathways were identi ed among PAH subgroups and control tissues. Spermine levels were positively correlated with the patients' cardiac outputs (COs). Levels of (2e)-2,5-dichloro-4-oxo-2-hexenedioic acid were positively correlated with the patient's serum creatinine (Scr) levels. Patients with higher levels of thymine had a better prognosis. Moreover, 7 differential metabolites were associated with AKT pathway. AKT pathway inactivation was con rmed in human and rat PAH lungs and hypoxia exposed HPASMCs.Conclusions: Our ndings provide the rst metabolomics evidence for PAH pathogenesis by human lungs and may contribute to the improvement of therapeutic strategy.

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Hemeoxygenase-1 Mediates an Adaptive Response to Spermidine-Induced Cell Death in Human Endothelial Cells

Cited by 14 publications

References 40 publications

Role of CREB on heme oxygenase-1 induction in adrenal cells: involvement of the PI3K pathway

Role of CREB on heme oxygenase-1 induction in adrenal cells: involvement of the PI3K pathway

Heme oxygenase (HO)-1 induction prevents Endoplasmic Reticulum stress-mediated endothelial cell death and impaired angiogenic capacity

Metabolomics-based mechanism exploration of pulmonary arterial hypertension pathogenesis: novel lessons from explanted human lungs

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