MilliporeSigma
  • Home
  • Search Results
  • Fatty acid receptor Gpr40 mediates neuromicrovascular degeneration induced by transarachidonic acids in rodents.

Fatty acid receptor Gpr40 mediates neuromicrovascular degeneration induced by transarachidonic acids in rodents.

Arteriosclerosis, thrombosis, and vascular biology (2013-03-23)
Jean-Claude Honoré, Amna Kooli, David Hamel, Thierry Alquier, José-Carlos Rivera, Christiane Quiniou, Xin Hou, Elsa Kermorvant-Duchemin, Pierre Hardy, Vincent Poitout, Sylvain Chemtob
ABSTRACT

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. 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. 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Arachidonic acid, >95.0% (GC)
Sigma-Aldrich
Arachidonic acid, from non-animal source, ≥98.5% (GC)
Sigma-Aldrich
Arachidonic acid sodium salt, from Porcine liver, ≥99% (capillary GC), waxy solid