A(1) and A(3) adenosine receptors inhibit LPS-induced hypoxia-inducible factor-1 accumulation in murine astrocytes

作者：Gessi Stefania; Merighi Stefania^*; Stefanelli Angela; Fazzi Debora; Varani Katia; Borea Pier Andrea

来源：Pharmacological Research, 2013, 76: 157-170.

DOI：10.1016/j.phrs.2013.08.002

• Hypoxia
• Astrocytes
• Inflammation
• HIF-1
• Adenosine receptors

Adenosine (Ado) exerts neuroprotective and anti-inflammatory functions by acting through four receptor subtypes A(1), A(2A), A(2B) and A(3). Astrocytes are one of its targets in the central nervous system. Hypoxia-inducible factor-1 (HIF-1), a master regulator of oxygen homeostasis, is induced after hypoxia, ischemia and inflammation and plays an important role in brain injury. HIF-1 is expressed by astrocytes, however the regulatory role played by Ado on HIF-1 alpha modulation induced by inflammatory and hypoxic conditions has not been investigated. %26lt;br%26gt;Primary murine astrocytes were activated with lipopolysaccharide (LPS) with or without Ado, Ado receptor agonists, antagonists and receptor silencing, before exposure to normoxia or hypoxia. HIF-1 alpha accumulation and downstream genes regulation were determined. %26lt;br%26gt;Ado inhibited LPS-increased HIF-1 alpha accumulation under both normoxic and hypoxic conditions, through activation of A(1) and A(3) receptors. In cells incubated with the blockers of p44/42 MAPK and Akt, LPS-induced HIF-1 alpha accumulation was significantly decreased in normoxia and hypoxia, suggesting the involvement of p44/42 MAPK and Akt in this effect and Ado inhibited kinases phosphorylation. A series of angiogenesis and metabolism related genes were modulated by hypoxia in an HIF-1 dependent way, but not further increased by LPS, with the exception of GLUT-1 and hexochinase II that were elevated by LPS only in normoxia and inhibited by Ado receptors. Instead, genes involved in inflammation, like inducible nitric-oxide synthase (iNOS) and A(2)B receptors, were increased by LPS in normoxia, strongly stimulated by LPS in concert with hypoxia and inhibited by Ado, through A(1) and A(3) receptor subtypes. In conclusion A(1) and A(3) receptors reduce the LPS-mediated HIF-1 alpha accumulation in murine astrocytes, resulting in a downregulation of genes involved in inflammation and hypoxic injury, like iNOS and A(2)B receptors, in both normoxic and hypoxic conditions.

• 出版日期2013-10