2014 Aug 1. pii: S0167-4889(14)00282-1. doi: 10.1016/j.bbamcr.2014.07.005. [Epub ahead of print]
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 nervous system and peripherally. 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-dopamines metabolism might prove useful for prevention against hypoxic diseases.
Copyright © 2014 Elsevier B.V. All rights reserved.
Copyright © 2014 Elsevier B.V. All rights reserved.
KEYWORDS:
Endogenous lipid mediators; hypoxia; neuroprotection; signal transduction
- PMID:
- 25090972
- [PubMed – as supplied by publisher]
