title: Adenosine modifies the balance between membrane and soluble forms of Flt-1.
abstract: VEGFR-1 (or Flt-1) exists under a sFlt-1 or a mFlt-1 form. sFlt-1 is antiangiogenic, and mFlt-1 is proangiogenic. The cardioprotective nucleoside Ado is proangiogenic, but its effects on Flt-1 are unknown and were tested in this study. In primary human macrophages from healthy volunteers, Ado inhibited sFlt-1 expression induced by LPS (-43%, P=0.006), HS, and IL-1β but not hypoxia. This effect was also observed in macrophages from patients with acute MI (-33%, P<0.001). It was reproduced by the A(2A) Ado receptor agonist CGS21680 and abrogated by the A(2A) antagonist SCH58261. Conversely, Ado increased mFlt-1 expression, thus switching sFlt-1 from the soluble toward the membrane form. This switch was also present in macrophages from acute MI patients (P<0.001). Assessment of HIF-1α nuclear translocation and activation together with siRNA experiments suggested that the effect of Ado on Flt-1 involves HIF-1α. In conclusion, Ado down-regulates sFlt-1 and up-regulates mFlt-1 production, an effect that indicates that Ado may be used to stimulate angiogenesis in the heart.
authors: Centre de Recherche Public-Santé, 120 route d'Arlon, L1150 Luxembourg.
authors: Frederique
authors: F
authors: Leonard
authors: Yvan
authors: Y
authors: Devaux
authors: Melanie
authors: M
authors: Vausort
authors: Isabelle
authors: I
authors: Ernens
authors: Magali
authors: M
authors: Rolland-Turner
authors: Daniel R
authors: DR
authors: Wagner
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D015151:Immunoblotting; D008264:Macrophages / Q000378:metabolism*; D009203:Myocardial Infarction / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012995:Solubility; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D040281:Vascular Endothelial Growth Factor Receptor-1; D000241:Adenosine