Heme Oxygenase-1 Inhibits the Expression of Adhesion Molecules Associated with Endothelial Cell Activation via Inhibition of NF-κB <i>RelA</i> Phosphorylation at Serine 276

Seldon, Mark P.; Silva, Gabriela; Pejanovic, Nadja; Larsen, Rasmus; Grégoire, Isabel Pombo; Filipe, Josina; Anrather, Josef; Soares, Miguel P.

doi:10.4049/jimmunol.179.11.7840

Cited by 128 publications

(106 citation statements)

References 60 publications

(88 reference statements)

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“…The PI3K/Akt pathway elicits a survival signal against apoptotic insults 26 Bcl-2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 31 ; Production of iron limits transcription of proinflammatory genes by inhibiting phosphorylation of NF-κB p65 32 ; Biliverdin may also serve as an antioxidant 29 . In vitro studies using neuronal cultures have shown that HO-1 protects neurons against oxidative injury 33 .…”

Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 Mediates Neuroprotection Conferred by Argon in Combination with Hypothermia in Neonatal Hypoxia–Ischemia Brain Injury

et al. 2016

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Background Hypoxic–ischemic encephalopathy is a major cause of mortality and disability in the newborn. The authors investigated the protective effects of argon combined with hypothermia on neonatal rat hypoxic–ischemic brain injury. Methods In in vitro studies, rat cortical neuronal cell cultures were challenged by oxygen and glucose deprivation for 90 min and exposed to 70% Ar or N2 with 5% CO2 balanced with O2, at 33°C for 2 h. Neuronal phospho-Akt, heme oxygenase-1 and phospho-glycogen synthase kinase-3β expression, and cell death were assessed. In in vivo studies, neonatal rats were subjected to unilateral common carotid artery ligation followed by hypoxia (8% O2 balanced with N2 and CO2) for 90 min. They were exposed to 70% Ar or N2 balanced with oxygen at 33°, 35°, and 37°C for 2 h. Brain injury was assessed at 24 h or 4 weeks after treatment. Results In in vitro studies, argon–hypothermia treatment increased phospho-Akt and heme oxygenase-1 expression and significantly reduced the phospho-glycogen synthase kinase-3β Tyr-216 expression, cytochrome C release, and cell death in oxygen–glucose deprivation–exposed cortical neurons. In in vivo studies, argon–hypothermia treatment decreased hypoxia/ischemia-induced brain infarct size (n = 10) and both caspase-3 and nuclear factor-κB activation in the cortex and hippocampus. It also reduced hippocampal astrocyte activation and proliferation. Inhibition of phosphoinositide-3-kinase (PI3K)/Akt pathway through LY294002 attenuated cerebral protection conferred by argon–hypothermia treatment (n = 8). Conclusion Argon combined with hypothermia provides neuroprotection against cerebral hypoxia–ischemia damage in neonatal rats, which could serve as a new therapeutic strategy against hypoxic–ischemic encephalopathy.

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Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 Mediates Neuroprotection Conferred by Argon in Combination with Hypothermia in Neonatal Hypoxia–Ischemia Brain Injury

et al. 2016

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“…7,8 In order to assess if ARE-driven HO-1 expression can have antiinflammatory effects in endothelial cells, we first examined its effect on NF-kB activation assessed by the activation of the NF-kB-regulated luciferase-reporter construct. To this end, cells were transduced with either an empty lentiviral control vector having only the phosphoglycerate kinase (PGK) promoter but no transgene, or 2 Â GCLM-HO-1 vector together with the NFkB-luciferase-reporter construct.…”

Section: Lentiviral Transduction Of Are-ho-1 Decreases the Induction mentioning

confidence: 99%

“…In endothelial cells, adenoviral overexpression of HO-1 has been shown to inhibit tumor necrosis factor (TNF)-a-induced activation of nuclear factor (NF)-kB and vascular cell adhesion molecule-1 (VCAM-1) expression. 7,8 For an optimal therapeutic response, it would be beneficial if the transgene expression could be regulated in order to turn the gene expression on and off when needed. This can be accomplished through the use of promoters that can be activated by orally administered drugs, such as tetracycline.…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress-inducible lentiviral vectors for gene therapy

Hurttila

Kansanen

et al. 2008

Gene Ther

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Oxidative stress is important in several pathologies, including cardiovascular diseases such as atherosclerosis and cardiac ischemia-reperfusion injury. An important mechanism for adaptation to oxidative stress is induction of genes through the antioxidant response element (ARE), which regulates the expression of antioxidant and cytoprotective genes via the transcription factor Nrf2 (nuclear factor E2-related factor 2). As Nrf2-regulated genes are induced during oxidant stress occurring, for example, in reperfusion after ischemia, we took a novel approach to exploit ARE for the development of oxidative stress-inducible gene therapy vectors. To this end, one, two or three ARE-containing regions from human NAD(P)H:quinone oxidoreductase-1, glutamate-cysteine ligase modifier subunit and mouse heme oxygenase-1 were cloned into a vector expressing luciferase under a minimal SV40 promoter. The construct, which was the most responsive to ARE-inducing agents, was chosen for further studies in which a lentiviral vector was produced for an efficient transfer to endothelial cells. Heme oxygenase-1 (HO-1), which has well-characterized anti-inflammatory properties, was used as the therapeutic transgene. In human endothelial cells, AREdriven HO-1 overexpression inhibited nuclear factor-kB activation and subsequent vascular cell adhesion molecule-1 expression induced by tumor necrosis factor-a. We conclude that the ARE element is a promising alternative for the development of oxidative stress-inducible gene therapy vectors.

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“…Frequent loss of FHIT in tumors is well documented. 5,9,16,29 Of equal significance, FHIT inactivation occurs early in the process of carcinogenesis, particularly in lung cancer, 18,30 suggesting that loss of this gene may facilitate acquisition of the additional alterations required for cell transformation.…”

Section: Introductionmentioning

confidence: 99%

“…20,32 However, expression of a catalytically inactive Hmox1 mutant promotes cell survival after stress as well as the wild type protein, suggesting that Hmox1 cytoprotection functions through an independent, yet to be elucidated mechanism. 28,33 Early events that occur after Hmox1 expression include increased cell proliferative capacity, 29,34 decreased cell adhesion, 30,35 increased migration potential, 31,35,36 and evasion of apoptosis. 32,37 It follows that HMOX1 overexpression is detected in many cancers, including prostate malignancies, melanoma, glioma, adenocarcinoma, and others.…”

Section: Introductionmentioning

confidence: 99%

A knockdown with smoke model reveals FHIT as a repressor of Heme oxygenase 1

Boylston

Brenner²

2014

Cell Cycle

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Fragile histidine triad (FHIT) gene deletions are among the earliest and most frequent events in carcinogenesis, particularly in carcinogen-exposed tissues. Though FHIT has been established as an authentic tumor suppressor, the mechanism underlying tumor suppression remains opaque. Most experiments designed to clarify FHIT function have analyzed the consequence of re-expressing FHIT in FHIT-negative cells. However, carcinogenesis occurs in cells that transition from FHIT-positive to FHIT-negative. To better understand cancer development, we induced FHIT loss in human bronchial epithelial cells with RNA interference. Because FHIT is a demonstrated target of carcinogens in cigarette smoke, we combined FHIT silencing with cigarette smoke extract (CSE) exposure and measured gene expression consequences by RNA microarray. The data indicate that FHIT loss enhances the expression of a set of oxidative stress response genes after exposure to CSE, including the cytoprotective enzyme heme oxygenase 1 (HMOX1) at the RNA and protein levels. Data are consistent with a mechanism in which Fhit protein is required for accumulation of the transcriptional repressor of HMOX1, Bach1 protein. We posit that by allowing superinduction of oxidative stress response genes, loss of FHIT creates a survival advantage that promotes carcinogenesis.

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Heme Oxygenase-1 Inhibits the Expression of Adhesion Molecules Associated with Endothelial Cell Activation via Inhibition of NF-κB RelA Phosphorylation at Serine 276

Cited by 128 publications

References 60 publications

Heme Oxygenase-1 Mediates Neuroprotection Conferred by Argon in Combination with Hypothermia in Neonatal Hypoxia–Ischemia Brain Injury

Heme Oxygenase-1 Mediates Neuroprotection Conferred by Argon in Combination with Hypothermia in Neonatal Hypoxia–Ischemia Brain Injury

Oxidative stress-inducible lentiviral vectors for gene therapy

A knockdown with smoke model reveals FHIT as a repressor of Heme oxygenase 1

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