title: Hypoximimetic activity of N-acyl-dopamines. N-arachidonoyl-dopamine stabilizes HIF-1α protein through a SIAH2-dependent pathway.
abstract: The N-acyl conjugates of amino acids and neurotransmitters (NAANs) are a class of endogenous lipid messengers that are expressed in the mammalian central and peripheral nervous system. Hypoxia inducible factor-1α (HIF-1α) is a transcription factor that plays a key role in the cellular adaptation to hypoxia and ischemia, and hypoxic preconditioning through HIF-1α has been shown to be neuroprotective in ischemic models. This study showed that N-acyl-dopamines induce HIF-1α stabilization on human primary astrocytes and neurons as well as in transformed cell lines. N-arachidonoyl-dopamine (NADA)-induced HIF-1α stabilization depends on the dopamine moiety of the molecule and is independent of cannabinoid receptor-1 (CB1) and transient receptor potential vanilloid type I (TRPV1) activation. NADA increases the activity of the E3 ubiquitin ligase seven in absentia homolog-2 (SIAH2), inhibits prolyl-hydroxylase-3 (PHD3) and stabilizes HIF-1α. NADA enhances angiogenesis in endothelial vascular cells and promotes the expression of genes such as erythropoietin (EPO), vascular endothelial growth factor A (VEGFA), heme oxygenase 1 (HMOX-1), hexokinase 2 (HK2) and Bcl-2/E1B-nineteen kiloDalton interacting protein (BNIP3) in primary astrocytes. These findings indicate a link between N-acyl-dopamines and hypoxic preconditioning and suggest that modulation of the N-acyl-dopamine metabolism might prove useful for prevention against hypoxic diseases.
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/ Hospital Universitario Reina Sofía/ Universidad de Córdoba, Córdoba, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Soler-Torronteras
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/ Hospital Universitario Reina Sofía/ Universidad de Córdoba, Córdoba, Spain.
authors.forename: Maribel
authors.initials: M
authors.lastname: Lara-Chica
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/ Hospital Universitario Reina Sofía/ Universidad de Córdoba, Córdoba, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: García
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/ Hospital Universitario Reina Sofía/ Universidad de Córdoba, Córdoba, Spain. Electronic address: mcalzado@uco.es.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Calzado
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/ Hospital Universitario Reina Sofía/ Universidad de Córdoba, Córdoba, Spain. Electronic address: e.munoz@uco.es.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Muñoz
keywords: Endogenous lipid mediator; Hypoxia; Neuroprotection; Signal transduction