Lysophosphatidic acid acts on LPA1 receptor to increase H2 O2 during flow-induced dilation in human adipose arterioles. Br J Pharmacol 2018 Nov;175(22):4266-4280
Date
08/29/2018Pubmed ID
30153326Pubmed Central ID
PMC6193883DOI
10.1111/bph.14492Scopus ID
2-s2.0-85054757437 (requires institutional sign-in at Scopus site) 12 CitationsAbstract
BACKGROUND AND PURPOSE: NO produces arteriolar flow-induced dilation (FID) in healthy subjects but is replaced by mitochondria-derived hydrogen peroxide (mtH2 O2 ) in patients with coronary artery disease (CAD). Lysophosphatidic acid (LPA) is elevated in patients with risk factors for CAD, but its functional effect in arterioles is unknown. We tested whether elevated LPA changes the mediator of FID from NO to mtH2 O2 in human visceral and subcutaneous adipose arterioles.
EXPERIMENTAL APPROACH: Arterioles were cannulated on glass micropipettes and pressurized to 60 mmHg. We recorded lumen diameter after graded increases in flow in the presence of either NOS inhibition (L-NAME) or H2 O2 scavenging (Peg-Cat) ± LPA (10 μM, 30 min), ±LPA1 /LPA3 receptor antagonist (Ki16425) or LPA2 receptor antagonist (H2L5186303). We analysed LPA receptor RNA and protein levels in human arterioles and human cultured endothelial cells.
KEY RESULTS: FID was inhibited by L-NAME but not Peg-Cat in untreated vessels. In vessels treated with LPA, FID was of similar magnitude but inhibited by Peg-Cat while L-NAME had no effect. Rotenone attenuated FID in vessels treated with LPA indicating mitochondria as a source of ROS. RNA transcripts from LPA1 and LPA2 but not LPA3 receptors were detected in arterioles. LPA1 but not LPA3 receptor protein was detected by Western blot. Pretreatment of vessels with an LPA1 /LPA3 , but not LPA2 , receptor antagonist prior to LPA preserved NO-mediated dilation.
CONCLUSIONS AND IMPLICATIONS: These findings suggest an LPA1 receptor-dependent pathway by which LPA increases arteriolar release of mtH2 O2 as a mediator of FMD.
Author List
Chabowski DS, Kadlec AO, Ait-Aissa K, Hockenberry JC, Pearson PJ, Beyer AM, Gutterman DDAuthors
Andreas M. Beyer PhD Associate Professor in the Medicine department at Medical College of WisconsinPaul Joseph Pearson MD, PhD Chief, Professor in the Surgery department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Adipose TissueAged
Arterioles
Cells, Cultured
Dilatation
Female
Humans
Hydrogen Peroxide
Lysophospholipids
Male
Middle Aged
Mitochondria
Receptors, Lysophosphatidic Acid
