Role of nitric oxide in the regulation  of HIF-1α expression during hypoxia

Agani, Faton; Puchowicz, Michelle A.; Chávez, Juan C.; Pichiule, Paola; LaManna, Joseph C.

doi:10.1152/ajpcell.00381.2001

Cited by 128 publications

(83 citation statements)

References 54 publications

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“…Our study supports that the HIF-1␣ expression was increased in the pressure-overloaded LV. On the other hand, the role of sGC-cGMP signaling in modulating HIF-1␣ and VEGF expressions is reported to be dependent on oxygen supply (1,5,20,27). In the present study, BAY 41-2272 had little effect on the HIF-1␣ expression under normoxic conditions, but the compound significantly inhibited the expression under the hypoxia in cultured cardiomyocytes.…”

Section: Discussioncontrasting

confidence: 47%

Pharmacological stimulation of soluble guanylate cyclase modulates hypoxia-inducible factor-1α in rat heart

Tsuruda¹,

Hatakeyama

Masuyama³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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. Pharmacological stimulation of soluble guanylate cyclase modulates hypoxia-inducible factor-1␣ in rat heart. Am J Physiol Heart Circ Physiol 297: H1274 -H1280, 2009. First published August 14, 2009 doi:10.1152/ajpheart.00503.2009.-Mechanical load and ischemia induce a series of adaptive physiological responses by activating the expression of O 2-regulated genes, such as hypoxia inducible factor-1␣ (HIF-1␣). The aim of this study was to explore the interaction between HIF-1␣ and soluble guanylate cyclase (sGC) and its second messenger cGMP in cultured cardiomyocytes exposed to hypoxia and in pressure-overloaded heart. In cultured cardiomyocytes of neonatal rats, either sGC stimulator BAY 41-2272 or cGMP analog 8-bromo-cGMP decreased the hypoxia (1% O 2/5% CO 2)-induced HIF-1␣ expression, whereas the inhibition of protein kinase G by KT-5823 reversed the effect of BAY 41-2272 on the expression under hypoxic conditions. In pressure-overloaded heart induced by suprarenal aortic constriction (AC) in 7-wk-old male Wistar rats, the administration of BAY 41-2272 (2 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) for 14 days significantly suppressed the protein expression of HIF-1␣ (P Ͻ 0.05), vascular endothelial growth factor (P Ͻ 0.01), and the number of capillary vessels (P Ͻ 0.01) induced by pressure overload. This study suggests that the pharmacological sGC-cGMP stimulation modulates the HIF-1␣ expression in response to hypoxia or mechanical load in the heart. cyclic guanosine monophosphate; hypoxia; mechanical load; angiogenesis; inflammation THE MYOCARDIUM IS AN elastic network of cardiomyocytes enmeshed in a collagen matrix that connects the myocytes and supporting intramyocardial coronary vasculature. Mechanical load or ischemia induces a series of adaptive physiological responses in the heart [cardiomyocyte hypertrophy, interstitial fibrosis, and angiogenesis (24, 29)]. Hypoxia inducible factor-1 (HIF-1) is one of the most important transcription factors, composed of following subunits: a constitutively expressed HIF-1␤ and HIF-1␣ induced by hypoxia, and the latter subunit induces the expression of a number of downstream genes, including that for the vascular endothelial growth factor (VEGF) (26). Expressions of HIF-1␣ and VEGF are reported to be activated in hypertrophied and failing heart (17,26,29,30), and the increased number of capillary vessels penetrating the interstitial spaces contribute to supply oxygen and nutrients to the cardiocytes for maintaining the structure and function of pressure-overloaded heart (29, 34).Guanylate cyclase is an enzyme that converts guanosine triphosphate to cyclic guanosine monophosphate (cGMP). Soluble guanylate cyclase (sGC) activated by nitric oxide has been shown to attenuate cardiovascular remodeling by elevating intracellular cGMP levels (6, 18). We and others have previously reported that the pharmacological stimulation of sGC with BAY 41-2272 attenuated the adverse remodeling associated with systemic or pulmonary hypertension, suggesting that sGC-cGMP activation would be one of the impor...

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Section: Discussioncontrasting

confidence: 47%

Pharmacological stimulation of soluble guanylate cyclase modulates hypoxia-inducible factor-1α in rat heart

Tsuruda¹,

Hatakeyama

Masuyama³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…Hypoxia-inducible factor 1␣ (HIF1␣) participates in the immediate early response to oxygen deprivation (Gassmann and Wenger 1997) and triggers the induction of several hypoxia-associated molecules (Agani et al 2002). Among these molecules, it has recently been demonstrated that HIF1␣ is associated with neuronal nitric oxide synthase (nNOS) and (i)Hsp70 is associated with the inducible form (iNOS) (Bellmann et al 2000).…”

Section: Introductionmentioning

confidence: 99%

Effects of hypoxia on stress proteins in the piglet heart at birth

Louapre

Grongnet²,

Tanguay

et al. 2005

Cell Stress Chaper

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Hypoxia at birth represents a very stressful event that can result in severe lifelong consequences in different tissues, including those of the heart. Heat shock and other associated stress proteins are involved in cellular protection, but their roles are not clearly defined at the time of birth. Newborn piglets were subjected to 5% oxygen and 95% nitrogen for either 1 or 4 hours. They were allowed to recover over periods of 1 to 68 hours. The relative levels of ␣B-crystallin, HspB8, Hsp20, Hsp27, Hsp60, and Hsp70 as well as nitric oxide synthases (NOS) (endothelial NOS, inducible NOS, neuronal NOS) were examined by Western blot analysis. Surprisingly, ␣B-crystallin expression was drastically increased in animals submitted to hypoxia. The hypoxia-associated factor HIFI␣ was also strongly and rapidly overexpressed. Heme oxygenase 1 was also increased. To a lesser extent, neuronal NOS was also increased in the left ventricle of animals submitted to hypoxia. This work clearly shows that the Hsp chaperone ␣B-crystallin is strongly overexpressed in the left ventricle of animals submitted to hypoxia. This observation dissociates the response to low oxygenation of ␣B-crystallin and other stress-associated proteins including Hsp27, and it indicates that heme oxygenase is not alone among HSPs in its oxygen-related gene expression.

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“…There is evidence that HIF activity is regulated by small molecules other than dioxygen and 2OG, including nitric oxide (17)(18)(19)(20), ascorbate (21), TCAIs (22)(23)(24), and reactive oxidizing species (25)(26)(27)(28). The mechanisms by which these compounds mediate a physiologically relevant effect, if indeed they do, are not yet established.…”

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confidence: 99%

Structural and Mechanistic Studies on the Inhibition of the Hypoxia-inducible Transcription Factor Hydroxylases by Tricarboxylic Acid Cycle Intermediates

Hewitson

Liénard

McDonough

et al. 2007

Journal of Biological Chemistry

205

184

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In humans both the levels and activity of the ␣-subunit of the hypoxia-inducible transcription factor (HIF-␣) are regulated by its post-translation hydroxylation as catalyzed by iron-and 2-oxoglutarate (2OG)-dependent prolyl and asparaginyl hydroxylases (PHD1-3 and factor-inhibiting HIF (FIH), respectively). One consequence of hypoxia is the accumulation of tricarboxylic acid cycle intermediates (TCAIs). In vitro assays were used to assess non-2OG TCAIs as inhibitors of purified PHD2 and FIH. Under the assay conditions, no significant FIH inhibition was observed by the TCAIs or pyruvate, but fumarate, succinate, and isocitrate inhibited PHD2. Mass spectrometric analyses under nondenaturing conditions were used to investigate the binding of TCAIs to PHD2 and supported the solution studies. X-ray crystal structures of FIH in complex with Fe(II) and fumarate or succinate revealed similar binding modes for each in the 2OG co-substrate binding site. The in vitro results suggest that the cellular inhibition of PHD2, but probably not FIH, by fumarate and succinate may play a role in the Warburg effect providing that appropriate relative concentrations of the components are achieved under physiological conditions.In humans and other mammals, the ␣␤ heterodimeric hypoxia-inducible transcription factor (HIF) 4 (1) regulates the oxygen-dependent transcription of an array of genes, including those encoding for enzymes involved in glycolysis and those proteins involved in oxygen delivery. The HIF-␤ subunit (HIF-␤) is identical to aryl hydrocarbon nuclear translocator, and its levels are oxygen-independent. Both the levels and transcriptional activity of the ␣-subunit (HIF-␣) are oxygen-regulated, and hydroxylation of human HIF-␣ at one of two prolyl residues (Pro-402 or Pro-564 in human HIF-1␣) (2, 3) within the oxygen-dependent degradation domain enables binding of HIF-␣ to the von Hippel-Lindau protein, the targeting element of an ubiquitin-protein isopeptide ligase complex. Subsequent ubiquitylation leads to proteasomal degradation of HIF-␣ (for recent reviews see Refs. 4 -7). In humans this mechanism is augmented by hydroxylation of an asparaginyl residue in the C-terminal transcriptional activation domain of HIF-1␣ (8); this modification blocks the interaction of HIF-1␣ with the transcriptional co-activator CBP/p300 so disabling HIF-mediated transcription. During hypoxia, the reduction or ablation of HIF hydroxylase activity leads to accumulation of HIF-1␣, dimerization with HIF-1␤, and consequent transcription of genes involved in the hypoxic response. Hydroxylation of human HIF-1␣ is catalyzed by four Fe(II)-and 2-oxoglutarate (2OG)-dependent dioxygenases (9, 10), which use molecular oxygen and the tricarboxylic acid cycle intermediate (TCAI) 2OG as co-substrates to produce CO 2 and the TCAI succinate as co-products (Fig. 1). Of the HIF hydroxylases, i.e. three prolyl hydroxylases (PHD1, -2, and -3) (11-13) and one asparaginyl hydroxylase (factor-inhibiting HIF (FIH)) (8, 14), PHD2 is proposed to be the most important...

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Role of nitric oxide in the regulation of HIF-1α expression during hypoxia

Cited by 128 publications

References 54 publications

Pharmacological stimulation of soluble guanylate cyclase modulates hypoxia-inducible factor-1α in rat heart

Pharmacological stimulation of soluble guanylate cyclase modulates hypoxia-inducible factor-1α in rat heart

Effects of hypoxia on stress proteins in the piglet heart at birth

Structural and Mechanistic Studies on the Inhibition of the Hypoxia-inducible Transcription Factor Hydroxylases by Tricarboxylic Acid Cycle Intermediates

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