Cellular Response to Hypoxia

So far, the best-studied adaptation of mammalian cells to variations in the oxygen availability is the response to hypoxia. Once exposed to low oxygen, chemoreceptor cells of the carotid body initiate a ventilatory response which should compensate the decreased 02 supply in the lung. Furthermore, the vasculature in the lung contracts, whereas the peripheral vasculature dilates, resulting in more efficient perfusion and gas exchange. Enhanced expression of erythropoietin (EPO) in the kidney and, to some extent, in the liver results in increased erythropoiesis in the bone marrow and in an elevation in the blood's 02-carrying capacity.

Figure 2. Models of an 02 sensing system. An 02-sensing system which modulates gene activity should ideally consist of an 02 sensor (S) which should possess enzymatic activity and may be ideally situated at the cell membrane. From the 02 sensor a signal is transmitted to a regulatory transcription factor (TF) which should possess DNA or RNA binding ability to modulate gene activity. The transmission of the 02 signal can involve several chemical modifications of the regulator either mediated directly by the sensor or indirectly via the generation of a second messenger such as H202. In the case that the sensor contains a kinase or oxygenase activity, the regulatory TF will be phosphorylated or hydroxylated. If the sensor contains an oxidase, oxygen intermediates such as H202 may be generated as second messengers leading then to the modification of the regulatory TF. The chemical modifications of the regulatory TF would then modify its binding affinity to response elements (RE) in the promoters or regulatory sites of certain genes, thus leading to a modification in their transcription.

Figure 2. Models of an 02 sensing system. An 02-sensing system which modulates gene activity should ideally consist of an 02 sensor (S) which should possess enzymatic activity and may be ideally situated at the cell membrane. From the 02 sensor a signal is transmitted to a regulatory transcription factor (TF) which should possess DNA or RNA binding ability to modulate gene activity. The transmission of the 02 signal can involve several chemical modifications of the regulator either mediated directly by the sensor or indirectly via the generation of a second messenger such as H202. In the case that the sensor contains a kinase or oxygenase activity, the regulatory TF will be phosphorylated or hydroxylated. If the sensor contains an oxidase, oxygen intermediates such as H202 may be generated as second messengers leading then to the modification of the regulatory TF. The chemical modifications of the regulatory TF would then modify its binding affinity to response elements (RE) in the promoters or regulatory sites of certain genes, thus leading to a modification in their transcription.

Additionally, various types oforgans and tissues increase the expression of vascular endothelial growth factor (VEGF) and its receptors to promote angiogenesis, thereby improving blood supply to tissue. Moreover, increased expression of glycolytic enzymes elevates the efficiency of anaerobic ATP generation. Besides these more general responses evolved to enhance 02 supply and to maintain energy provision, many other physiological and pathophysiological processes are known to be regulated by 02. This is illustrated by the increasing number of genes encoding transporters, enzymes, hormones and growth factors which are expressed differentially (i.e., higher or lower) under conditions of low Po2 (hypoxia) compared to normoxia (Table 1).

Table 1. Examples of Processes and Genes Activated by Hypoxia

Processes

Hematopoesis Angiogcncsis Fibrinolysis Inflammation Growtli and Differentiation

Carbohydrate metabolism Glucose transport Glycolysis

NHj-amino acid metabolism Xen obi otic metabolism Heme metabolism H20- and electrolyte regulation_

Hypoxia-induced gene Rcf,

Erythropoietin (EPO) 29

Vase u lar endoth el ial growth fac tor (V E G F) 30

Plasminogen activator inhibitor-1 (PALI) 55

Inducible nitric oxide synthase (iNOS) 73

p53 Tumor-suppress or protein 34

Be 1-2 apop tos is-p re venting protein 92

Insulin-like growth factor binding protein-1 (IGFBP-1) 98

Glucose transport er-1 (GLUT-1) 28

Glucokinase (GK) 19,24,25,54,89,90 Aldolase A (ALD-A)

Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) Phosphoglycerate kinase 1 (PGK.1) Pyruvate kinase M (PKM) Lactate dehydrogenase A (LDH-A)

L-Arginine transporter 67

Heme oxygenase-1 (HO-1) 64

Angiotensin converting enzyme (ACE) 58

A special case ofthe response to hypoxia is the so called anoxic response, i.e., the response to a Po2 very close to 0 mmHg. This response is best studied in lower vertebrates such as turtles which can live for months under water without ventilation because of their drastically reduced protein synthesis, and thus 02 consumption, which allows the survival of cellular functions under extreme conditions (42). Similarly, a reduction of protein synthesis was also observed after stroke in the peri-infarct area (penumbra) of the brain, facilitating cell survival by oxygen sensing (91).

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