title: Fatty acid receptor Gpr40 mediates neuromicrovascular degeneration induced by transarachidonic acids in rodents.
abstract: OBJECTIVE
  Nitro-oxidative stress exerts a significant role in the genesis of hypoxic-ischemic (HI) brain injury. We previously reported that the ω-6 long chain fatty acids, transarachidonic acids (TAAs), which are nitrative stress-induced nonenzymatically generated arachidonic acid derivatives, trigger selective microvascular endothelial cell death in neonatal neural tissue. The primary molecular target of TAAs remains unidentified. GPR40 is a G protein-coupled receptor activated by long chain fatty acids, including ω-6; it is highly expressed in brain, but its functions in this tissue are largely unknown. We hypothesized that TAAs play a significant role in neonatal HI-induced cerebral microvascular degeneration through GPR40 activation.
  
  
  RESULTS
  Within 24 hours of a HI insult to postnatal day 7 rat pups, a cerebral infarct and a 40% decrease in cerebrovascular density was observed. These effects were associated with an increase in nitrative stress markers (3-nitrotyrosine immunoreactivity and TAA levels) and were reduced by treatment with nitric oxide synthase inhibitor. GPR40 was expressed in rat pup brain microvasculature. In vitro, in GPR40-expressing human embryonic kidney (HEK)-293 cells, [(14)C]-14E-AA (radiolabeled TAA) bound specifically, and TAA induced calcium transients, extracellular signal-regulated kinase 1/2 phosphorylation, and proapoptotic thrombospondin-1 expression. In vivo, intracerebroventricular injection of TAAs triggered thrombospondin-1 expression and cerebral microvascular degeneration in wild-type mice, but not in GPR40-null congeners. Additionally, HI-induced neurovascular degeneration and cerebral infarct were decreased in GPR40-null mice.
  
  
  CONCLUSIONS
  GPR40 emerges as the first identified G protein-coupled receptor conveying actions of nonenzymatically generated nitro-oxidative products, specifically TAAs, and is involved in (neonatal) HI encephalopathy.
authors.affiliation: Department of Pediatrics, Research Center-CHU Ste-Justine, Montréal, Quebec, Canada.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Honoré
authors.forename: Amna
authors.initials: A
authors.lastname: Kooli
authors.forename: David
authors.initials: D
authors.lastname: Hamel
authors.forename: Thierry
authors.initials: T
authors.lastname: Alquier
authors.forename: José-Carlos
authors.initials: JC
authors.lastname: Rivera
authors.forename: Christiane
authors.initials: C
authors.lastname: Quiniou
authors.forename: Xin
authors.initials: X
authors.lastname: Hou
authors.forename: Elsa
authors.initials: E
authors.lastname: Kermorvant-Duchemin
authors.forename: Pierre
authors.initials: P
authors.lastname: Hardy
authors.forename: Vincent
authors.initials: V
authors.lastname: Poitout
authors.forename: Sylvain
authors.initials: S
authors.lastname: Chemtob
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002544:Cerebral Infarction / Q000209:etiology*; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000150:complications; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*
chemical_list: C473036:Ffar1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D016718:Arachidonic Acid