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7.5 Hypoxia and Adenosine
Hypoxia, in addition to stabilization of HIF-1
, also increases intracel-
lular and extracellular levels of adenosine (Fig. 7.2). Extracellularly, adenosine is
produced by degradation of ATP by ectonucleotidases like CD39 (ATPDase) and
CD73 (ecto-5 -nucleotidase). Hypoxia, through an SP1 dependent mechanism, can
increase expression of CD39, which catalyzes hydrolysis of ATP and ADP [20].
HIF-1
α
and HIF-2
α
increases the expression of CD73 that catalyzes the conversion of AMP
to adenosine [70]. Intracellular adenosine, under normoxic resting conditions, is
either converted to AMP by adenosine kinase or degraded to inosine by adenosine
deaminase. Hypoxia can inhibits both adenosine kinase and adenosine deaminase
[51] resulting in intracellular adenosine accumulation. Additionally, hypoxia also
regulates expression of adenosine transporters ENT1 and ENT2, through a HIF-
1
α
dependent mechanism [21]. Therefore multiple parallel pathways contribute to
increased adenosine concentrations in hypoxia.
Biological activity of adenosine is mediated through its binding to four different
adenosine receptors, A 1 ,A 2A ,A 2B and A 3 [4]. While A 1 and A 3 receptors inhibit
α
HYPOXIA
Sp1
HIF-1
AMP
Adenosine
Sp1
ADP
HIFs
CD73
CD39
ATP
A 2A /A 2B
receptor
CD39
HIF-1
ENT
(Equilibrative
Nucleoside
Transporter)
ATP
ADP
Adenosine
Adenosine
ki na se
Inosine
AMP
Adenosine
dea m inase
SAH
hydrolase
Hypoxia
Hypoxia
SAH
(S-adenosyl homocysteine)
Fig. 7.2 Hypoxic regulation of adenosinergic signaling in a typical cell. Hypoxia causes both
intracellular and extracellular levels of adenosine to increase. Extracellularly, adenosine is formed
by the hydrolysis of ATP to adenosine. Two enzymes in this pathway, CD39 and CD73 are
transcriptionally upregulated by hypoxia. While CD39 is regulated by hypoxia through an Sp1
dependent mechanism, CD73 is regulated by HIF-1 α . Besides hydrolysis of ATP, intracellular
levels of adenosine are also affected by adenosine kinase and adenosine deaminase that convert
adenosine to AMP and inosine respectively. Hypoxia inhibits both of these enzymes leading to
increased accumulation of adenosine. Intracellular and extracellular levels of adenosine are also
maintained through the hypoxia and HIF-1
α
regulatable nucleoside transporters. Cell surface
receptors for adenosine, the A 2A and A 2B receptors, are also regulated by hypoxia and HIFs. Solid
arrows indicate transcriptional upregulation by hypoxia and/or HIFs
 
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