A₁ and A₃ adenosine receptors inhibit LPS-induced hypoxia-inducible factor-1 accumulation in murine astrocytes

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• 作者：Stefania Gessi ; Stefania Merighi ; Angela Stefanelli ; Debora Fazzi ; Katia Varani ; Pier Andrea Borea
• 关键词：ActD ; actinomycin D ; Ado ; adenosine ; ADA ; adenosine deaminase ; BAY 60-6583 ; 2-[[6-amino-3 ; 5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]-2-pyridinyl]thio]-acetamide ; CHA ; N(6)-cyclohexyladenosine ; CGS 21680 ; 2-p-(2-carboxyethyl)phenethylamino-5&prime ; -N-ethyl
• 刊名：Pharmacological Research
• 出版年：2013
• 出版时间：October, 2013
• 年：2013
• 卷：76
• 期：Complete
• 页码：157-170
• 全文大小：3106 K

文摘

Adenosine (Ado) exerts neuroprotective and anti-inflammatory functions by acting through four receptor subtypes A₁, A_2A, A_2B and A₃. 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¦Á modulation induced by inflammatory and hypoxic conditions has not been investigated.

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¦Á accumulation and downstream genes regulation were determined.

Ado inhibited LPS-increased HIF-1¦Á accumulation under both normoxic and hypoxic conditions, through activation of A₁ and A₃ receptors. In cells incubated with the blockers of p44/42 MAPK and Akt, LPS-induced HIF-1¦Á 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_2B receptors, were increased by LPS in normoxia, strongly stimulated by LPS in concert with hypoxia and inhibited by Ado, through A₁ and A₃ receptor subtypes. In conclusion A₁ and A₃ receptors reduce the LPS-mediated HIF-1¦Á accumulation in murine astrocytes, resulting in a downregulation of genes involved in inflammation and hypoxic injury, like iNOS and A_2B receptors, in both normoxic and hypoxic conditions.