Human platelets respond differentially to lysophosphatidic acids having a highly unsaturated fatty acyl group and alkyl ether-linked lysophosphatidic acids.
Lysophosphatidic acid (LPA) is a physiological agonist that is produced by lysophospholipase D, phospholipase A(1) and phospholipase A(2) in the blood of animals. It exerts diverse biological actions on a broad range of animal cells. Specific receptors for this important agonist have been characterized. In this investigation, for the first time we prepared LPAs having a highly unsaturated fatty acyl group, such as the eicosapentaenoyl or docosahexaenoyl residue, and their acetylated derivatives. Human platelets aggregated more potently in response to the highly unsaturated acyl-LPAs than to LPAs with a C(18) fatty acyl group, such as an oleoyl group, while alkyl ether-linked LPAs (alkyl-LPA) had much stronger aggregating activity. Two positional isomers of LPAs with an arachidonoyl, eicosapentaenoyl or docosahexaenoyl group had equipotent aggregatory activity as well as the positional isomers of their acetylated analogues, indicating that putative LPA receptors could not distinguish the difference between the positional isomers. We found that platelet preparations from two individuals showed no aggregatory response to alkyl-LPAs, although they contained mRNAs for known LPA receptors in the following order of expression level: endothelial differentiation gene (Edg)-4>Edg-7>Edg-2. We also obtained evidence that 2-(p-amylcinnamoyl)amino-4-chlorobenzoic acid (ONO-RS-082), a phospholipase A(2) inhibitor, potentiated alkyl-LPA-induced platelet aggregation, but inhibited highly unsaturated acyl-LPA-induced platelet aggregation. These results indicated that human platelets express acyl-LPA-selective and alkyl-LPA-selective receptors on their plasma membrane.
Tokumura
Akira
A
Faculty of Pharmaceutical Sciences, The University of Tokushima, 1-78 Shomachi, Tokushima 770-8505, Japan. tokumura@ph.tokushima-u.ac.jp
Sinomiya
Junya
J
Kishimoto
Seishi
S
Tanaka
Tamotsu
T
Kogure
Kentaro
K
Sugiura
Takayuki
T
Satouchi
Kiyoshi
K
Waku
Keizo
K
Fukuzawa
Kenji
K
D000345:Affinity Labels / Q000378:metabolism; D062365:Aminobenzoates / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D002723:Chlorobenzoates; D002934:Cinnamates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005231:Fatty Acids, Unsaturated / Q000737:chemistry*; D008401:Gas Chromatography-Mass Spectrometry; D005995:Glyceryl Ethers / Q000737:chemistry*; D006801:Humans; D008246:Lysophospholipids / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D062367:ortho-Aminobenzoates
D000345:Affinity Labels; D062365:Aminobenzoates; D002723:Chlorobenzoates; D002934:Cinnamates; D005231:Fatty Acids, Unsaturated; D005995:Glyceryl Ethers; D008246:Lysophospholipids; D009687:Nuclear Proteins; D010726:Phosphodiesterase Inhibitors; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D014157:Transcription Factors; D062367:ortho-Aminobenzoates; D012710:Serum Albumin, Bovine; C060048:2-(4-amylcinnamoyl)amino-4-chlorobenzoic acid