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Hypobaric Hypoxia: Adaptation and Acclimatization
Published in Anthony N. Nicholson, The Neurosciences and the Practice of Aviation Medicine, 2017
John H. Coote, James S. Milledge
All these actions within the carotid body are dependent on another oxygen-sensitive protein, the hypoxia-inducible factor 1 (HIF-1α). It has been shown that an increase in ventilatory drive, measured from activity in the phrenic nerve, induced by an hypoxic stimulus of the carotid body (but not aortic body), is impaired in heterozygous mice bred with a partial deficit in HIF-1α expression (Kline et al., 2002; Peng et al., 2006). The regulatory pathways controlling HIF-1 are illustrated in Figure 7.2. The oxygen-regulated HIF-1α sub-unit is one part of a heterodimeric protein that is also comprised of a constitutively expressed HIF-1β sub-unit. The level of HIF-1α increases with hypoxia due to depression of the oxygen-requiring enzyme prolyl hydroxylase that breaks down HIF-1α when sufficient oxygen is present.
Principles and Biological Pathways to Tissue Regeneration: The Tissue Regenerative Niche
Published in Claudio Migliaresi, Antonella Motta, Scaffolds for Tissue Engineering, 2014
Ranieri Cancedda, Claudia Lo Sicco
HIF-1 is composed by two subunits, where the subunit beta is constitutively expressed, whereas the subunit alpha is an oxygen-sensitive inducible protein. Under sufficient oxygen concentration (normoxic condition), prolyl-hydroxylase enzymes add hydroxyl groups to two proline residues of the HIF-1-alpha. The prolyl-hydroxilated HIF-1-alpha is recognized by the von Hippel-Lindau protein, which adds a destruction molecular tag (polyubiquitination) to the HIF-1-alpha [Giaccia et al., 2004]. Under limited oxygen conditions the degradation rate decreases, and HIF-1-alpha protein accumulates and associates with HIF-1-beta to form a functional transcription complex [Hewitson and Schofield, 2004]. The active HIF-1 transcription factor induces the expression of several survival genes counteracting hypoxia, including gene coding for angiogenic factors [Potier et al., 2007].
Overview of Angiogenesis: Molecular and Structural Features
Published in Robert J. Gropler, David K. Glover, Albert J. Sinusas, Heinrich Taegtmeyer, Cardiovascular Molecular Imaging, 2007
Arye Elfenbein, Michael Simons
HIF-1α is degraded under normoxic conditions by a proteosome-dependent pathway, but hypoxia confers stability that enables the protein to accumulate intracellularly. This occurs because the baseline degradation of HIF-1α depends on its post-translational modification, a process that requires oxygen as a cofactor. The Von Hippel-Lindau protein (a member of the ubiquitin ligase family) marks HIF-1α for subsequent degradation only if HIF-1α is post-translationally modified by prolyl hydroxylase-containing enzymes (4). By requiring oxygen (as well as ascorbic acid and iron), prolyl hydroxylase function ultimately results in the modulation of intracellular HIF-1α concentration. Under hypoxic conditions, hydroxylation of HIF-1α is therefore ineffective, the protein becomes less readily degraded, and it subsequently accumulates in the cell.
The study on the inhibitory mechanism of JTZ-951 and its analogue against prolyl hydroxylase-2 to mediate the response to hypoxia in the process of sports
Published in Molecular Physics, 2021
Tao Li, Song Wang, Hao Zhang, Jiankang Yu
Recent studies showed that hypoxia inducible factor (HIF) is the critical factor for the expression of EPO in the red blood cell system. HIF consists of two subunits, an oxygen regulated α subunit (HIF-α) and a constitutively expressed β subunit (HIF-β). HIF modulates the various gene expression including EPO, angiogenesis, vascular tone, glucose metabolism, cell proliferation [4,5]. The hypoxia-associated transcription activity of HIF can be regulated metabolically by the dioxygenases, namely prolyl hydroxylases (PHD) having three subtypes (PHD 1-3) [6,7]. The C4 trans hydroxylation of HIF-α at PRO-402 and PRO-564 are realised based on the transcription activity of HIF by using 2-oxoglutarate (2-OG), O2 and Fe(II) as cofactors [8]. This mechanism shows that the hydroxylation of HIF-α is inhibited by PHDs during hypoxia in the process of sports, leading to the stabilisation of HIF-α and adaptation to hypoxia [9,10]. Thus, inhibitors targeting to PHDs may increase the EPO levels due to the stabilisation of HIF-α. Furthermore, it has been widely believed that PHD-2 is the key factor in controlling the transcription of HIF among three PHDs [11]. In fact, PHD-2 has become the promising target to mediate the level of EPO for the HIF-related diseases recently [12]. Furthermore, based on the crystallography method, the structural information of PHD-2 was explored. The binding sites of substrate and hydroxylation site were identified [13–15].