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Year : 2019  |  Volume : 18  |  Issue : 2  |  Page : 59-62

Hypoxia-inducible factors-α as a regulator for forkhead box protein M1 in pulmonary artery hypertension

Department of Clinical Laboratory Science, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq

Date of Submission09-Jun-2019
Date of Decision30-Sep-2019
Date of Acceptance25-Oct-2019
Date of Web Publication18-Dec-2019

Correspondence Address:
Dr. Israa Burhan Raoof
Department of Clinical Laboratory Science, College of Pharmacy, Mustansiriyah University, Baghdad
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/MJ.MJ_12_19

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Hypoxia is defined as decreased levels of oxygen in the cells, which are caused by vascular and pulmonary diseases. The catalysts of hypoxia in the physiological role are important in all living cells, whereas its metabolic dysfunction is related to many diseases. Hypoxia-inducible factors (HIFs) activity should be controlled by providing HIF modules. Forkhead box protein M1 (FOXM1) plays a crucial role in the maintenance and differentiation of airways epithelial cell lining, especially during embryonic life, where it is essential in the formation and proliferation of pulmonary vessels. FOXM1 is overexpressed in the pulmonary artery smooth muscle in response to hypoxia through the elements that are present in the promoters of FOXM1; therefore, it was used to diagnose patients with pulmonary artery hypertension.

Keywords: Forkhead box protein M1, Hypoxia-inducible factors, pulmonary artery hypertension

How to cite this article:
Raoof IB, Daoud AG. Hypoxia-inducible factors-α as a regulator for forkhead box protein M1 in pulmonary artery hypertension. Mustansiriya Med J 2019;18:59-62

How to cite this URL:
Raoof IB, Daoud AG. Hypoxia-inducible factors-α as a regulator for forkhead box protein M1 in pulmonary artery hypertension. Mustansiriya Med J [serial online] 2019 [cited 2023 Jun 8];18:59-62. Available from: https://www.mmjonweb.org/text.asp?2019/18/2/59/273343

  Introduction Top

Forkhead box protein M1 (FOXM1) has four subtypes (FOXM1a, FOXM1b, FOXM1c, and FOXM1d), which are transcription factors except FOXM1a.[1] It plays the role as a transcription factor through the activation of signaling pathways by targeting genes that control cell cycle processes such as cellular differentiation, cellular proliferation, cellular renewal, cellular migration, cellular survival, angiogenesis, and repairs damaged DNA.[1],[2] FOXM1 plays a crucial role in the maintenance and differentiation of airways epithelial cell lining,[3] especially during embryonic life, where it is essential in the formation and proliferation of pulmonary vessels.[4] Pulmonary artery hypertension (PAH) results from alteration in the pulmonary artery smooth muscle cells (SMCs) type from contractile phenotype into proliferative ones and remodeling of vasculature. It is stimulated by hypoxia-inducible factors (HIFs), including two types: HIF1a and HIF2a.[5],[6],[7] FOXM1 is overexpressed in the pulmonary artery SMCs in response to hypoxia through the elements that are present in the FOXM1 promoters. Besides, reduced expression of miR-204, which in turn leads to the expression of FOXM1 from these cells in patients with PAH.[8],[9] Under normal circumstances, HIF-1a regulates the action of FOXM1, whereas in the case of hypoxia, FOXM1 is stimulated by HIF-2a in the SMCs of the pulmonary arteries [5] by binding with target genes.[10] As a result, FOXM1 is induced by both HIF-1a and HIF-2a isoforms, but they differ in their response to oxygen (according to its concentration) and their distribution in the tissues.[5] In addition to HIF, there are other factors which are also thought to play an important role in the expression of FOXM1 in the SMCs enhancing their proliferation, and PAH includes CXCL12, PDGF-B, ET-1, or MIF,[11] which lead to hypertrophy of the right ventricle and remodeling of pulmonary artery SMCs;[7] furthermore, increase the number of endothelial cells in patients with PAH.[12] FoxM1 has an essential role in the controlling proliferation of SMCs; therefore, it is very necessary to understand the importance of FoxM1 in pulmonary hypertension and to illustrate the molecular mechanisms of it.[5] HIFs stimulated by the low level of oxygen supply in the cells by a special transcriptional program.[13] The deficiency of oxygen in the cells and tissues results from imbalance between metabolic requirements and oxygen availability, for example, during vigorous exercise or embryos growing, ischemia and cancer which reduced consumption of oxygen by metabolic alterations and intensifying the mechanisms responsible for transferring oxygen to cells such as erythrocyte regulation and angiogenesis, and these modifications are involved increased levels of gene expression.[14],[15] There are three types of hypoxia: acute hypoxia, hypoxia reperfusion, and chronic hypoxia. In chronic hypoxia, the percentage of oxygen stress is about 2%–3%, especially cause unlimited cell proliferation. There are two types of hypoxia, acute hypoxia and hypoxia reperfusion, observed in these types, increase oxidative stress and blood toxicity.[16] The expression of HIF-1α in the macrophages increased by internal inflammation, atheroma, and arteries wall thickness often exceed the oxygen limit to 100–200 μm,[5] which may develop to plaques formation by affecting on low-density lipoprotein-cholesterol flow and apoptosis. On the other hand, primary inflammatory genes, influence on the secretion of monocyte chemoattractant protein-1 from cells,[17] and partially induces vascular endothelial growth factor expression, in addition to glycolysis stimulation and glucose transporter by hexokinase and lactate dehydrogenase both promote glucose conversion to pyruvate by dehydrogenase, which inhibits the carboxylic acid cycle; therefore, unstable hypoxia may lead to increased mitochondrial activity, resulting in accumulation of reactive oxygen species and deregulation of cellular energetic as shown in [Figure 1].[18]
Figure 1: Hypoxia inducible factors are involved in several metabolisms[18]

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When hypoxia or other stimuli are stable, HIF-1-α is associated with HIF-1-β transferred to a nucleus, the heterodimer is then linked to the HRE sequence and the p300 helper starts to copy the target gene, the removal of copper using tetraethylenepentamine stimulate FIH-1, leads to HIF-1 hydroxylation and prevents its binding to the p300. It also reduces the HIF-1 link in the target gene sequence and inhibits transcription activity by CCS. In this regard, copper can be converted from FIH-1 activity to maintain the binding capacity of HIF-1 as shown in [Figure 2].[19]
Figure 2: Copper chelating by TEPA on hypoxia-inducible factor-1 transactivity.[19] VEGF: Vascular endothelial growth factor, TEPA: Tetraethylenepentamine, HRE: Hypoxia-responsive element, FIH-1: Factor inhibiting hypoxia-inducible factor 1, CCS: Copper chaperone for superoxide dismutase 1, PHD: Hypoxia-inducible factor prolyl hydroxylase

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Scientists explain all these mechanisms by protein translation according to low intracellular oxygen.[20] HIF is catalyzed in response to hypoxia in the cells and tissues, which new drugs are HIF prolyl-hydroxylase inhibitors used to regulate HIF in chronic renal anemia.[21] New clinical factors depending on the hypoxia-inducible factor mechanism stimulate erythropoietin to increase iron concentration by physiological action to treat anemia.[22] Correspondence studies suggest that cells distribution of HIF-prolyl hydroxylases between the cytosol and the nucleus plays a role in the management of chronic kidney anemia, but irregular distribution of HIF-prolyl hydroxylases cells between these compartments is responded to hypoxia condition.[23]

Hypoxia upregulates FOXM1 expression in SMCs through elevated growth factor and inflammatory cytokine from endothelial cells, and the increased FOXM1 targets different pathways, such as increasing SMC and proliferation, inhibition of SMC differentiation and apoptosis, resulting in PAH vascular remodeling as shown in [Figure 3].[24]
Figure 3: Forkhead box protein M1 promotes pulmonary arterial hypertension progression and initiation.[24] PDGF-B: Platelet-derived growth factor, ET-1: Endothelin-1, MIF: Macrophage migration inhibitory factor, CXCL12: Chemokine ligand 12, SMC Smooth muscle cell, NBS1: Nijmegen breakage syndrome 1

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  Conclusion Top

  1. Hypoxia is an important factor in the development of PAH through the stimulation of FOXM1 expression in SMCs of the pulmonary artery in addition to that hypoxia also occurs in the other types of pulmonary hypertension
  2. Protein translation is stimulated according to low oxygen levels inside the cells, playing a role in the pulmonary hypertension progression
  3. The expression of HIF-1α in the macrophages increases internal inflammation and stimulates atheroma formation and arteries wall thickness.


The authors extend their deep thanks to Mustansiriyah University for their support of this work.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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Ustiyan V, Wang IC, Ren X, Zhang Y, Snyder J, Xu Y, et al. Forkhead box M1 transcriptional factor is required for smooth muscle cells during embryonic development of blood vessels and esophagus. Dev Biol 2009;336:266-79.  Back to cited text no. 4
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Courboulin A, Paulin R, Giguère NJ, Saksouk N, Perreault T, Meloche J, et al. Role for miR-204 in human pulmonary arterial hypertension. J Exp Med 2011;208:535-48.  Back to cited text no. 8
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Xia LM, Huang WJ, Wang B, Liu M, Zhang Q, Yan W, et al. Transcriptional up-regulation of foxM1 in response to hypoxia is mediated by HIF-1. J Cell Biochem 2009;106:247-56.  Back to cited text no. 10
Dai Z, Zhu MM, Peng Y, Jin H, Machireddy N, Qian Z, et al. Endothelial and smooth muscle cell interaction via foxM1 signaling mediates vascular remodeling and pulmonary hypertension. Am J Respir Crit Care Med 2018;198:788-802.  Back to cited text no. 11
Guignabert C, Tu L, Le Hiress M, Ricard N, Sattler C, Seferian A, et al. Pathogenesis of pulmonary arterial hypertension: Lessons from cancer. Eur Respir Rev 2013;22:543-51.  Back to cited text no. 12
Påhlman S, Mohlin S. Hypoxia and hypoxia-inducible factors in neuroblastoma. Cell Tissue Res 2018;372:269-75.  Back to cited text no. 13
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Aarup A, Pedersen TX, Junker N, Christoffersen C, Bartels ED, Madsen M, et al. Hypoxia-inducible factor-1α expression in macrophages promotes development of atherosclerosis. Arterioscler Thromb Vasc Biol 2016;36:1782-90.  Back to cited text no. 17
Chen C, Lou T. Hypoxia inducible factors in hepatocellular carcinoma. Oncotarget 2017;8:46691-703.  Back to cited text no. 18
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  [Figure 1], [Figure 2], [Figure 3]

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