Modulation of hypoxia-inducible factors (HIF) from an integrative pharmacological perspective

Rodríguez‐Jiménez, Francisco Javier; Moreno‐Manzano, Victoria

doi:10.1007/s00018-011-0813-4

Cited by 13 publications

(7 citation statements)

References 180 publications

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“…As previously mentioned, HIF-1a and HIF-2a synthesis can be regulated through NF-kB, but their activity is controlled by PH enzymes that, under normal oxygen tensions, target HIF-a for degradation (7,25). Our data showed a synergistic response in Hb-induced HIF activity when HMECs-1 were cotreated with DMOG, a competitive inhibitor of PH enzyme.…”

Section: Tlr4 (supporting

confidence: 69%

Hemoglobin-Induced Endothelial Cell Permeability Is Controlled, in Part, via a Myeloid Differentiation Primary Response Gene–88–Dependent Signaling Mechanism

Lisk¹,

Kominsky²,

Ehrentraut³

et al. 2013

Am J Respir Cell Mol Biol

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The release of hemoglobin (Hb) with hemolysis causes vascular dysfunction. New evidence implicates Hb-induced NF-kB and hypoxia inducible factor (HIF) activation, which may be under the control of a Toll-like receptor (TLR)-signaling pathway. Nearly all TLR-signaling pathways activate the myeloid differentiation primary response gene-88 (MyD88) that regulates NF-kB. We hypothesized that the differing transition states of Hb influence endothelial cell permeability via NF-kB activation and HIF regulation through a MyD88-dependent pathway. In cultured human dermal microvascular endothelial cells (HMECs-1), we examined the effects of Hb in the ferrous (HbFe 21 ), ferric (HbFe 31 ), and ferryl (HbFe 41 ) transition states on NF-kB and HIF activity, HIF-1a and HIF-2a mRNA upregulation, and monolayer permeability, in the presence or absence of TLR4, MyD88, NF-kB, or HIF inhibition, as well as superoxide dismutase (SOD) and catalase. Our data showed that cell-free Hb, in each transition state, induced NF-kB and HIF activity, up-regulated HIF-1a and HIF-2a mRNA, and increased HMEC-1 permeability. The blockade of either MyD88 or NF-kB, but not TLR4, attenuated Hb-induced HIF activity, the up-regulation HIF-1 and HIF-2a mRNA, and HMEC-1 permeability. The inhibition of HIF activity exerted less of an effect on Hb-induced monolayer permeability. Moreover, SOD and catalase attenuated NF-kB, HIF activity, and monolayer permeability. Our results demonstrate that Hb-induced NF-kB and HIF are regulated by two mechanisms, either MyD88 activation or Hb transition state-induced ROS formation, that influence HMEC-1 permeability.Keywords: hemolytic disease; NF-kB; Toll-like receptors; MyD88; sicklecell disease Humans with chronic vascular inflammation and vasoconstriction develop progressive endothelial dysfunction and vascular diseases (e.g., pulmonary arterial hypertension, atherosclerosis, and sickle-cell disease) (1, 2). Vascular diseases develop in the face of chronic hemolysis, as occurs with hemoglobinopathies (including sickle-cell disease), or with the intermittent release of low to moderate levels of plasma-free hemoglobin (Hb), as may be seen in atherosclerosis with intraplaque hemorrhage.Low to moderate levels of plasma-free Hb may, in part, mediate these diseases (1-4). However, studies to date have not fully addressed the complete mechanisms responsible for Hb-induced vascular dysfunction.The a 2 b 2 tetramers of Hb transition safely and effectively between the relaxed (oxy) and tense (deoxy) conformational states, and the oxidation of Hb is controlled by red blood cell catalase, superoxide dismutase (SOD), and ferric Hb reductase. However, after their release from the red blood cell, Hb tetramers and dimers can be oxidized from ferrous (HbFe 21 ) to ferric (HbFe 31 ) (3-5). In theory, HbFe 31 in local tissue environments may react with hydrogen peroxide (H 2 O 2 ) to transition between the ferryl (HbFe 41 ) and HbFe 31 states, leading to heme release, globin chain denaturation, and globin chain crosslinking (4, 5). Oxid...

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Section: Tlr4 (supporting

confidence: 69%

Hemoglobin-Induced Endothelial Cell Permeability Is Controlled, in Part, via a Myeloid Differentiation Primary Response Gene–88–Dependent Signaling Mechanism

Lisk¹,

Kominsky²,

Ehrentraut³

et al. 2013

Am J Respir Cell Mol Biol

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“…Recombinant human Epo (rhEpo) and its analogues have been misused for doping purposes, [1,2] but their intake may be proven by drug testing [3,4] and they are expensive. [7] By this way, Co 2+ stimulates Epo production, as first observed in experimental animals in the late 1950s. [5] With respect to doping practices, of particular interest are cobalt (II) ions (Co 2+ ).…”

Section: Introductionmentioning

confidence: 70%

“…[6] Co 2+ activates the hypoxia-inducible transcription factors (HIFs) that increase EPO expression. [7] By this way, Co 2+ stimulates Epo production, as first observed in experimental animals in the late 1950s. [8] Co 2+ is the reference substance for the in vivo calibration of rhEpo drug substance; 5 μmol Co 2+ elicits the same erythropoiesis-stimulating activity as one International Unit (IU) of rhEpo.…”

Section: Introductionmentioning

confidence: 85%

Intolerability of cobalt salt as erythropoietic agent

Ebert¹,

Jelkmann²

2013

Drug Testing and Analysis

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Unfair athletes seek ways to stimulate erythropoiesis, because the mass of haemoglobin is a critical factor in aerobic sports. Here, the potential misuse of cobalt deserves special attention. Cobalt ions (Co(2+) ) stabilize the hypoxia-inducible transcription factors (HIFs) that increase the expression of the erythropoietin (Epo) gene. Co(2+) is orally active, easy to obtain, and inexpensive. However, its intake can bear risks to health. To elaborate this issue, a review of the pertinent literature was retrieved by a search with the keywords 'anaemia', 'cobalt', 'cobalt chloride', 'erythropoiesis', 'erythropoietin', 'Epo', 'side-effects' and 'treatment', amongst others. In earlier years, cobalt chloride was administered at daily doses of 25 to 300 mg for use as an anti-anaemic agent. Co(2+) therapy proved effective in stimulating erythropoiesis in both non-renal and renal anaemia, yet there were also serious medical adverse effects. The intake of inorganic cobalt can cause severe organ damage, concerning primarily the gastrointestinal tract, the thyroid, the heart and the sensory systems. These insights should keep athletes off taking Co(2+) to stimulate erythropoiesis.

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“…In order to drive gene transcription, HIF-1α directly interacts with the CBP/p300 complex which can then bind to target gene promoters (62). In addition to HIF-1α, CBP/p300 can interact with a wide variety of transcription factors; competition for a limiting quantity of CBP/p300 regulates transcriptional induction of HIF-1α targets (82, 83). We hypothesized that the lack of HIF-1α allowed other transcription factors to bind to CBP thus enhancing transcriptional induction of IL-10.…”

Section: Discussionmentioning

confidence: 99%

Inverse Correlation between IL-10 and HIF-1α in Macrophages Infected with Histoplasma capsulatum

Fecher

Horwath

Friedrich

et al. 2016

The Journal of Immunology

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Hypoxia inducible factor (HIF)-1α is a transcription factor that regulates metabolic and immune response genes in the setting of low oxygen tension and inflammation. We investigated the function of HIF-1α in the host response to Histoplasma capsulatum since granulomas induced by this pathogenic fungus develop hypoxic microenvironments during the early adaptive immune response. Here we demonstrated that myeloid HIF-1α-deficient mice exhibited elevated fungal burden during the innate immune response (prior to seven days post-infection) as well as decreased survival in response to a sublethal inoculum of H. capsulatum. The absence of myeloid HIF-1α did not alter immune cell recruitment to the lungs of infected animals but was associated with an elevation of the anti-inflammatory cytokine IL-10. Treatment with mAb to IL-10 restored protective immunity to the mutant mice. Macrophages (Mϕ) constituted the majority of IL-10 producing cells. Deletion of HIF-1α in neutrophils or DCs did not alter fungal burden thus implicating Mϕs as the pivotal cell in host resistance. HIF-1α was stabilized in Mϕ following infection. Increased activity of the transcription factor CREB in HIF-1α-deficient Mϕs drove IL-10 production in response to H. capsulatum. IL-10 inhibited Mϕ control of fungal growth in response to the activating cytokine IFN-γ. Thus, we identified a critical function for Mϕ HIF-1α in tempering IL-10 production following infection. We established that transcriptional regulation of IL-10 by HIF-1α and CREB is critical for activation of Mϕ by IFN-γ and effective handling of H. capsulatum.

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Modulation of hypoxia-inducible factors (HIF) from an integrative pharmacological perspective

Cited by 13 publications

References 180 publications

Hemoglobin-Induced Endothelial Cell Permeability Is Controlled, in Part, via a Myeloid Differentiation Primary Response Gene–88–Dependent Signaling Mechanism

Hemoglobin-Induced Endothelial Cell Permeability Is Controlled, in Part, via a Myeloid Differentiation Primary Response Gene–88–Dependent Signaling Mechanism

Intolerability of cobalt salt as erythropoietic agent

Inverse Correlation between IL-10 and HIF-1α in Macrophages Infected with Histoplasma capsulatum

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