Inhibition of Hypoxia-inducible Factor 1 Activation by Carbon Monoxide and Nitric Oxide

Huang, L. Eric; Willmore, William G.; Gu, Jie; Goldberg, Mark A.; Bunn, H. Franklin

doi:10.1074/jbc.274.13.9038

Cited by 286 publications

(195 citation statements)

References 49 publications

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“…We cannot exclude, however, that a chemical reaction of NO or one of its metabolites with PHD causes enzyme inactivation at a moiety other than Fe 2ϩ . A number of reports from independent groups suggested that treatment of cells with NO donors under hypoxic conditions inhibited HIF-1␣ accumulation and transactivation of HIF-1 (Liu et al, 1998;Sogawa et al, 1998;Huang et al, 1999). At present we do not have an explanation for the difference between normoxic and hypoxic NO effects.…”

Section: Discussionmentioning

confidence: 55%

“…Regulation of HIF-1 activity by NO is likely to be of (patho)-physiological relevance but molecular mechanisms have not been defined yet. Initial observations suggested that NO inhibits hypoxia-induced HIF-1␣ stabilization and HIF-1 transcriptional activation (Liu et al, 1998;Sogawa et al, 1998;Huang et al, 1999). More recent studies indicated that chemically diverse NO donors or enhanced endogenous NO formation by inducible NO-synthase or NO formation in a coculture system under normoxic conditions provoked HIF-1␣ stabilization, HIF-1 DNA-binding, and activation of downstream target gene expression (Kimura et al, 2001;Sandau et al, 2001aSandau et al, , 2001bZhou et al, 2003).…”

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confidence: 99%

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Nitric Oxide Impairs Normoxic Degradation of HIF-1α by Inhibition of Prolyl Hydroxylases

Metzen

Zhou

Jelkmann

et al. 2003

MBoC

375

261

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Hypoxia inducible factor-1 (HIF-1) is the master regulator of metabolic adaptation to hypoxia. It is appreciated that HIF-1␣ accumulation is achieved under normoxic conditions by e.g., nitric oxide. We determined molecular mechanisms of HIF-1␣ accumulation under the impact of S-nitrosoglutathione (GSNO). In human embryonic kidney cells GSNO provoked nuclear accumulation of HIF-1␣. This appeared unrelated to gene transcription and protein translation, thus pointing to inhibition of HIF-1␣ degradation. Indeed, GSNO as well as the hypoxia mimic CoCl 2 decreased ubiquitination of HIF-1␣ and GSNO-induced HIF-1␣ failed to coimmunoprecipitate with pVHL (von Hippel Lindau protein). Considering that HIF-1␣-pVHL interactions require prolyl hydroxylation of HIF-1␣, we went on to demonstrate inhibition of HIF-1␣ prolyl hydroxylases (PHDs) by GSNO. In vitro HIF-1␣-pVHL interactions revealed that GSNO dose-dependently inhibits PHD activity but not the interaction of a synthetic peptide resembling the hydroxylated oxygen-dependent degradation domain of HIF-1␣ with pVHL. We conclude that GSNO-attenuated prolyl hydroxylase activity accounts for HIF-1␣ accumulation under conditions of NO formation during normoxia and that PHD activity is subject to regulation by NO. INTRODUCTIONThe heterodimeric transcription factor hypoxia inducible factor-1 (HIF-1) plays a central role in adaptation to decreased oxygen availability (Semenza, 2002;Wenger, 2002;Brü ne and Zhou, 2003). HIF-1 is composed of the two basic helix-loop-helix-Per-Arnt-Sim (bHLH-PAS) proteins HIF-1␣ and the aryl hydrocarbon receptor nuclear translocator (ARNT), also known as HIF-1␤ (Wang and Semenza, 1995). In many cell types, the mRNA of both HIF-1␣ and HIF-1␤ appear permanently expressed and HIF-1␤ protein is constitutively present. However, HIF-1␣ protein is kept at a low or undetectable level under normoxia. In hypoxia, HIF-1␣ is strikingly induced, translocates to the nucleus, and dimerizes with HIF-1␤ to form HIF-1, which binds to hypoxiaresponsive elements (HRE) in regulatory regions of an impressive array of target genes involved in angiogenesis, erythropoiesis, vasomotor control, and energy metabolism as well as in cell survival decisions (for references, see Maxwell et al., 2001;Wenger, 2002; Zhu et al., 2002). This makes HIF-1 the master regulator of oxygen homeostasis to meet cell and tissue requirements in a situation of oxygen deficiency.In normoxia HIF-1␣ is bound to the von Hippel Lindau protein (pVHL) (Maxwell et al., 1999;Hon et al., 2002;Min et al., 2002), which is the substrate recognizing component of an E3 ubiquitin ligase complex (Cockman et al., 2000;Ohh et al., 2000;Tanimoto et al., 2000). Consequently, HIF-1␣ is polyubiquitinated and degraded by the 26S proteasome system, thus accounting for its low normoxic level of expression (Salceda and Caro, 1997;Huang et al., 1998;Kallio et al., 1999). The requirement of pVHL for HIF-1␣ degradation is underscored in cells that do not contain a functional pVHL, which leads to high levels of HIF-1␣ in normox...

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Section: Discussionmentioning

confidence: 55%

mentioning

confidence: 99%

Nitric Oxide Impairs Normoxic Degradation of HIF-1α by Inhibition of Prolyl Hydroxylases

Metzen

Zhou

Jelkmann

et al. 2003

MBoC

375

261

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“…The initial report indicated that NO inhibits stabilization of HIF1 under hypoxia 46 . The underlying mechanism for this effect does not appear to be mediated by nitrosylation of the cysteine residue in the ODD, although deletion of the ODD eliminates the effect of NO in downregulating HIF1α protein levels 47 . As detailed above, under aerobic conditions, NO nitrosylates this residue to prevent degradation of HIF1 (REF.…”

Section: Free Radical Regulation Of Hif1 Under Hypoxic Conditionsmentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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Hypoxia and free radicals, such as reactive oxygen and nitrogen species, can alter the function and/or activity of the transcription factor hypoxia-inducible factor 1 (HIF1). Interplay between free radicals, hypoxia and HIF1 activity is complex and can influence the earliest stages of tumour development. The hypoxic environment of tumours is heterogeneous, both spatially and temporally, and can change in response to cytotoxic therapy. Free radicals created by hypoxia, hypoxia-reoxygenation cycling and immune cell infiltration after cytotoxic therapy strongly influence HIF1 activity. HIF1 can then promote endothelial and tumour cell survival. As discussed here, a constant theme emerges: inhibition of HIF1 activity will have therapeutic benefit.Virchow first described the abnormal structure of tumour vessels using contrast agents in human tumours as early as the mid 1800s 1 . A few decades later, Goldman was among the first to suggest that angiogenesis was associated with tumour growth 2 . A number of other investigators in the nineteenth and early twentieth centuries evaluated tumour angiogenesis, using techniques such as microangiography, vascular casting and window chamber models. Warren has reviewed this early work in great detail 3 . Folkman illuminated the crucial role of tumour angiogenesis by hypothesizing that tumour growth was dependent upon angiogenesis and that, if angiogenesis could be inhibited, it could maintain tumour deposits in a quiescent state 4 . These early works set the stage for the concept that tumours require angiogenesis to provide a nutrient supply. Although it is well-established that angiogenesis occurs in nearly all human solid tumours, it does not occur in an efficient manner, leading to spatial and temporal inadequacies in delivery of oxygen and other nutrients. These inefficiencies in nutrient delivery lead to a brutal cycle of unsatisfied demand by the tumour, which drives continued aberrant angiogenesis.The transcription factor hypoxia-inducible factor 1 (HIF1) plays an important part in tumour progression by upregulating genes that control angiogenesis, meta-stasis and resistance to oxidative stress. It also controls the switch to anaerobic metabolism, which can maintain cell NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript viability under hypoxic conditions. Further, HIF1 activity can promote treatment resistance by promoting endothelial and tumour cell survival after cytotoxic therapy. The mechanisms that control HIF1 activity are complex and are influenced by microenvironmental factors involving hypoxia, oxidative and nitrosative stress.In this Review we will discuss four important and interrelated aspects of tumour hypoxia. First, we will define the hypoxic response, discussing its relevance in influencing tumour cell survival, behaviour and angiogenesis. We will examine the physiological factors that contribute to hypoxia, emphasizing a perspective based on spatial and temporal dysfunction of tumour microcirculation. The question of whethe...

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“…NO has been demonstrated to interact with several intracellular signaling cascades, including mitogenactivated protein kinase (MAPK), janus kinase (JAK) and Jun N-terminal kinase (JNK) (Lander, 1997;Kim et al, 1997;So et al, 1998). Additionally, transcription of several gene classes, including cytokines, matrix proteins and hormones, are modulated by NO regulation of nuclear factor κB (NFκB), hypoxia inducible factor 1 (HIF1) and zinc-finger transcription factors (Huang et al, 1999b;Kroncke and Carlberg, 2000;Matthews et al, 1996;Tabuchi et al, 1996;Torres and Forman, 2000). ROS, however, regulates transcription of protein kinases, growth factors and transcription factors, and plays a role in signaling in the vasculature (Burdon, 1996;Giaccia and Kastan, 1998;Maulik, 2002;Meyer et al, 1994;Nose, 2000).…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide modulates murine yolk sac vasculogenesis and rescues glucose induced vasculopathy

et al. 2004

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Nitric oxide (NO) has been demonstrated to mediate events during ovulation,pregnancy, blastocyst invasion and preimplantation embryogenesis. However,less is known about the role of NO during postimplantation development. Therefore, in this study, we explored the effects of NO during vascular development of the murine yolk sac, which begins shortly after implantation. Establishment of the vitelline circulation is crucial for normal embryonic growth and development. Moreover, functional inactivation of the endodermal layer of the yolk sac by environmental insults or genetic manipulations during this period leads to embryonic defects/lethality, as this structure is vital for transport, metabolism and induction of vascular development. In this study, we describe the temporally/spatially regulated distribution of nitric oxide synthase (NOS) isoforms during the three stages of yolk sac vascular development (blood island formation, primary capillary plexus formation and vessel maturation/remodeling) and found NOS expression patterns were diametrically opposed. To pharmacologically manipulate vascular development,an established in vitro system of whole murine embryo culture was employed. During blood island formation, the endoderm produced NO and inhibition of NO(L-NMMA) at this stage resulted in developmental arrest at the primary plexus stage and vasculopathy. Furthermore, administration of a NO donor did not cause abnormal vascular development; however, exogenous NO correlated with increased eNOS and decreased iNOS protein levels. Additionally, a known environmental insult (high glucose) that produces reactive oxygen species(ROS) and induces vasculopathy also altered eNOS/iNOS distribution and induced NO production during yolk sac vascular development. However, administration of a NO donor rescued the high glucose induced vasculopathy, restored the eNOS/iNOS distribution and decreased ROS production. These data suggest that NO acts as an endoderm-derived factor that modulates normal yolk sac vascular development, and decreased NO bioavailability and NO-mediated sequela may underlie high glucose induced vasculopathy.

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Inhibition of Hypoxia-inducible Factor 1 Activation by Carbon Monoxide and Nitric Oxide

Cited by 286 publications

References 49 publications

Nitric Oxide Impairs Normoxic Degradation of HIF-1α by Inhibition of Prolyl Hydroxylases

Nitric Oxide Impairs Normoxic Degradation of HIF-1α by Inhibition of Prolyl Hydroxylases

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Nitric oxide modulates murine yolk sac vasculogenesis and rescues glucose induced vasculopathy

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