Cellular and Molecular Defenses Against Hypoxia

Abstract

The ability to cope with hypoxia is essential for the development and survival of all vertebrate species. Cellular hypoxia occurs when oxygen demand exceeds oxygen supply. The development of cellular hypoxia depends both on the type of tissue and partial pressure oxygen (PO 2 ) in the tissue, because cells can vary extremely in their physiologic oxygen demand. Under normal conditions up to 90 % of the available oxygen is consumed by mitochondria to yield ATP through oxidative phosphorylation. Thus, oxygen deprivation will always lead to fundamental changes in cell metabolism and function. Different physiological systems have evolved for adaptation to conditions of low oxygen. Acute adaptation includes increased ventilation, changes in metabolism, protection against hypoxia-induced cell death and vasodilation. Adaptations to chronic hypoxia are characterized by the aim to restore oxygen delivery to the tissue. This is achieved by improving the oxygen transport capacity by increasing haemoglobin and red blood cell mass. Furthermore, long-term adaptation includes the remodelling of existing vessels as well as the formation of new vessels to increase blood and concurrently oxygen supply. Most of the hypoxic adaptations implicate gene expression driven by transcription factors especially activated under hypoxic conditions, such as H ypoxia-i nducible f actor 1 (HIF-1). HIF-1 is the best characterized regulators of cellular responses to hypoxia and products of its target genes are involved in all phases of hypoxic adaptation. In addition, for certain tissues a variety of HIF-1 independent molecular changes contributing to the cellular hypoxic response have been described including activation of NF-κB, CREB, and Notch. Particular attention is devoted to a potential cross talk between the oxygen-dependent HIF-1 regulators prolyl-hydroxylase (PHDs) and these HIF-1 independent hypoxia regulated factors which are known to be critical for survival under general stress conditions.

Whole-Genome Sequencing of Native Sheep Provides Insights into Rapid Adaptations to Extreme Environments

“…Among the candidate genes for the plateau adaptations, five ( IFNGR2 , MAPK4 , NOX4 , SLC2A4 , and PDK1 ) were located in the classical HIF-1 (hypoxia-induced factors) pathway, which plays a central role in regulating cellular responses to hypoxia ( Frede and Fandrey 2013 ); four were found in the corresponding downstream vascular endothelial growth factor (VEGF; RRAS and MAPK4 ) and glycolysis/gluconeogenesis ( KIF2A and KHSRP ) pathways; and five ( ARHGEF19 , STK17A , MAPK4 , PPP1R1A and PRKG1 ) were found in the vascular smooth muscle contraction (VSMC) pathway, which adjusts the diameter of blood vessels and the delivery of blood oxygen ( fig. 7 A ).…”

The Genome Landscape of Tibetan Sheep Reveals Adaptive Introgression from Argali and the History of Early Human Settlements on the Qinghai–Tibetan Plateau

“…Strong selective signals ( F ST ≥ 0.2722) were highlighted in eight genes ( EPO, TLR4, PIK3CA, PRKCA, EGLN3, EGLN2, IFNGR2 , and CUL2 ; fig. 6 A ) known to be important components of the HIF-1 (hypoxia-induced factors) pathway (Frede and Fandrey 2013), indicating potential roles for these genes in high-altitude hypoxia adaptation in Tibetan sheep. Specifically, one prominent candidate gene EPO encodes a secreted glycosylated cytokine and binds to the erythropoietin receptor to control erythrocyte production.…”

“…7 A ), which have been reported to affect high-altitude environment adaptation in humans and animals (Storz et al. 2009, 2010; Frede and Fandrey 2013; Natarajan et al. 2013; Projecto-Garcia et al.…”

“…2016). Whole-genome selective scans have identified positive selection on a set of genes (e.g., EPAS1 , EPO , EGLN1 , EGLN2 , and EGLN3 ) in the HIF-1 (hypoxia-induced factors) pathway associated with hypoxia response (Frede and Fandrey 2013) in humans (e.g., Tibetan, Simonson et al. 2010; Andean, Wolfson et al.…”

Comparative Analysis of Long Non-Coding RNA and mRNA Expression Provides Insights into Adaptation to Hypoxia in Tibetan Sheep

“…For a detailed description of the relevant functions and pathway to candidate genes see Table 1. Among them, three (PIK3R1, IGF1R and PDK1) were located in the classical HIF-1 pathway, which played a central role in regulating cellular responses to hypoxia [21][22][23]; ve were found in the corresponding downstream vascular endothelial growth factor (VEGF, FZD4 and IFNB2) and glycolysis/gluconeogenesis pathways (ATF3, PPCK1 and PFKFB2). The dysregulation of genes in these relevant pathways indicated that hypoxia-induced factors, angiogenesis, and glycolysis metabolism are the most important factors that allowed sheep to manage extreme hypoxic environmental pressure.…”