Akt-Mediated Activation of HIF-1 in Pulmonary Vascular Endothelial Cells by S-Nitrosoglutathione

Carver, Deborah Jeannean; Gaston, Benjamin; deRonde, Kimberly; Palmer, Lisa A.

doi:10.1165/rcmb.2006-0289sm

Cited by 43 publications

(29 citation statements)

References 48 publications

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“…HIF-1␣ is a master transcriptional regulator of the cellular response to hypoxia and induces genes such as VEGF that regulate angiogenesis. Although HIF-1␣ is degraded and undetectable in normoxic tissue, recent in vitro reports indicate that NO and GSNO can stabilize HIF-1␣ in normoxic conditions (17)(18)(19). We therefore hypothesized that deletion of GSNOR might lead to accumulation of HIF-1␣ in vivo under basal conditions.…”

Section: Resultsmentioning

confidence: 96%

Endogenous S -nitrosothiols protect against myocardial injury

Lima¹,

Lam

Xie

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

199

192

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Despite substantial evidence that nitric oxide (NO) and/or endogenous S-nitrosothiols (SNOs) exert protective effects in a variety of cardiovascular diseases, the molecular details are largely unknown. Here we show that following left coronary artery ligation, mice with a targeted deletion of the S-nitrosoglutathione reductase gene (GSNOR ؊/؊ ) have reduced myocardial infarct size, preserved ventricular systolic and diastolic function, and maintained tissue oxygenation. These profound physiological effects are associated with increases in myocardial capillary density and S-nitrosylation of the transcription factor hypoxia inducible factor-1␣ (HIF-1␣) under normoxic conditions. We further show that S-nitrosylated HIF-1␣ binds to the vascular endothelial growth factor (VEGF) gene, thus identifying a role for GSNO in angiogenesis and myocardial protection. These results suggest innovative approaches to modulate angiogenesis and preserve cardiac function.angiogenesis ͉ HIF-1␣ ͉ myocardial infarction ͉ nitric oxide ͉ S-nitrosylation

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Section: Resultsmentioning

confidence: 96%

Endogenous S -nitrosothiols protect against myocardial injury

Lima¹,

Lam

Xie

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

199

192

View full text Add to dashboard Cite

show abstract

“…During normoxia, GSNO has been reported to promote HIF-1a stabilization, due to S-nitrosylation of Cys533 within the oxygen-dependent degradation domain, to prevent HIF-1a degradation (48) or S-nitrosylation of Cys800, which supports interaction with the coactivator p300 protein (49), or by increased HIF-1a accumulation and activity by Akt signaling (50). In contrast, NO and S-nitrosothiols, such as GSNO, are also capable of inhibiting HIF-1 activity during hypoxia by inhibition of HIF-1 DNA binding and/or by restoration of prolyl hydroxylase enzyme activity (51,52).…”

Section: Discussionmentioning

confidence: 99%

Modulation of NF-κB and Hypoxia-Inducible Factor−1 byS-Nitrosoglutathione Does Not Alter Allergic Airway Inflammation in Mice

Olson

Kasahara²,

Hristova³

et al. 2011

Am J Respir Cell Mol Biol

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Induction of nitric oxide synthase (NOS)-2 and production of nitric oxide (NO) are common features of allergic airway disease. Conditions of severe asthma are associated with deficiency of airway S-nitrosothiols, a biological product of NO that can suppress inflammation by S-nitrosylation of the proinflammatory transcription factor, NF-kB. Therefore, restoration of airway S-nitrosothiols might have therapeutic benefit, and this was tested in a mouse model of ovalbumin (OVA)-induced allergic inflammation. Naive or OVAsensitized animals were administered S-nitrosoglutathione (GSNO; 50 ml, 10 mM) intratracheally before OVA challenge and analyzed 48 hours later. GSNO administration enhanced lung tissue S-nitrosothiol levels and reduced NF-kB activity in OVA-challenged animals compared with control animals, but did not lead to significant changes in total bronchoalveolar lavage cell counts, differentials, or mucus metaplasia markers. Administration of GSNO also altered the activation of hypoxia-inducible factor (HIF)-1, leading to HIF-1 activation in naive mice, but suppressed HIF-1 activation in OVA-challenged mice. We assessed the contribution of endogenous NOS2 in regulating NF-kB and/or HIF-1 activation and allergic airway inflammation using NOS2 2/2 mice. Although OVA-induced NF-kB activation was slightly increased in NOS2 2/2 mice, associated with small increases in bronchoalveolar lavage neutrophils, other markers of allergic inflammation and HIF-1 activation were similar in NOS2 2/2 and wildtype mice. Collectively, our studies indicate that instillation of GSNO can suppress NF-kB activation during allergic airway inflammation, but does not significantly affect overall markers of inflammation or mucus metaplasia, thus potentially limiting its therapeutic potential due to effects on additional signaling pathways, such as HIF-1.Keywords: nitric oxide; asthma; S-nitrosothiols; nuclear factor-kB; hypoxia inducible factor21Nitric oxide (NO) is a ubiquitous signaling molecule that is continuously produced within the airways of healthy individuals, primarily originating from constitutive expression of the inducible NO synthase (NOS)-2 (iNOS) within the respiratory epithelium (1, 2). Airway NO production is increased under conditions of infection or inflammation due to induction of NOS2. Indeed, induction of airway NOS2 and increased airway production of NO are common symptoms of allergic asthma, an inflammatory disease of the airways characterized by airway hyperreactivity, smooth muscle thickening, and mucus hypersecretion. Analysis of exhaled human breath has demonstrated higher levels of NO in patients with asthma compared with healthy control subjects, with increases in epithelial NOS2 being the primary site of its production (1, 2). Induction of NOS2 is critical in innate antimicrobial or antiviral host defense, but its contribution in conditions of airway inflammation, including allergic asthma, is still controversial, and includes both pro-and anti-inflammatory properties, based on studies with NOS2 inhibitors...

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“…In addition, low NO concentrations were reported to induce S-nitrosylation at Cys 83 , inhibiting PTEN enzymatic activity and thus stimulating the downstream Akt pathway. Similarly, the administration of GSNO to pulmonary arterial endothelial cells was reported to induce PTEN S-nitrosylation and activity inhibition reversible by dithiothreitol and ultraviolet light (8). Physiologically, the PTEN S-nitrosylation was observed in regions of ischemic mammalian brain with low NO concentrations (core and penumbra regions), while S-nitrosylated Akt was detected only at sites with high NO concentrations (ischemic core).…”

Section: Pten Nitrosylationmentioning

confidence: 96%

Reactive Nitrogen Species and Hydrogen Sulfide as Regulators of Protein Tyrosine Phosphatase Activity

Heneberg

2014

Antioxidants & Redox Signaling

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Significance: Redox modifications of thiols serve as a molecular code enabling precise and complex regulation of protein tyrosine phosphatases (PTPs) and other proteins. Particular gasotransmitters and even the redox modifications themselves affect each other, of which a typical example is S-nitrosylation-mediated protection against the further oxidation of protein thiols. Recent Advances: For a long time, PTPs were considered constitutively active housekeeping enzymes. This view has changed substantially over the last two decades, and the PTP family is now recognized as a group of tightly and flexibly regulated fundamental enzymes. In addition to the conventional ways in which they are regulated, including noncovalent interactions, phosphorylation, and oxidation, the evidence that has accumulated during the past two decades suggests that many of these enzymes are also modulated by gasotransmitters, namely by nitric oxide (NO) and hydrogen sulfide (H 2 S). Critical Issues: The specificity and selectivity of the methods used to detect nitrosylation and sulfhydration remains to be corroborated, because several researchers raised the issue of false-positive results, particularly when using the most widespread biotin switch method. Further development of robust and straightforward proteomic methods is needed to further improve our knowledge of the full extent of the gasotransmitters-mediated changes in PTP activity, selectivity, and specificity. Further Directions: Results of the hitherto performed studies on gasotransmitter-mediated PTP signaling await translation into clinical medicine and pharmacotherapeutics. In addition to directly affecting the activity of particular PTPs, the use of reversible S-nitrosylation as a protective mechanism against oxidative stress should be of high interest. Antioxid. Redox Signal. 20, 2191-2209.

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Akt-Mediated Activation of HIF-1 in Pulmonary Vascular Endothelial Cells by S-Nitrosoglutathione

Cited by 43 publications

References 48 publications

Endogenous S -nitrosothiols protect against myocardial injury

Endogenous S -nitrosothiols protect against myocardial injury

Modulation of NF-κB and Hypoxia-Inducible Factor−1 byS-Nitrosoglutathione Does Not Alter Allergic Airway Inflammation in Mice

Reactive Nitrogen Species and Hydrogen Sulfide as Regulators of Protein Tyrosine Phosphatase Activity

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