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
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DOI：
10.1161/atvbaha.112.300943
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发表时间：
2013-05-01
影响因子：
8.7
通讯作者：
Chemtob, Sylvain
中科院分区：
文献类型：
--
作者：
Honore, Jean-Claude;Kooli, Amna;Chemtob, Sylvain
Objective-Nitro-oxidative stress exerts a significant role in the genesis of hypoxic-ischemic (HI) brain injury. We previously reported that the omega-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 omega-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.Approach and 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, [C-14]-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. (Arterioscler Thromb Vasc Biol. 2013; 33: 954-961.)
