Objective-Lysophosphatidic acids (LPA) have important roles in the field of vascular biology and are derived mainly from lysophosphatidylcholine via autotaxin. However, in our previous study, only the plasma LPA levels, and not the serum autotaxin levels, increased in patients with acute coronary syndrome (ACS). The aim of this study was to elucidate the pathway by which LPA is increased in patients with ACS. Approach and Results-We measured the plasma lysophospholipids species in 141 consecutive patients undergoing coronary angiography (ACS, n=38; stable angina pectoris, n=71; angiographically normal coronary arteries, n=32) using a liquid chromatography-tandem mass spectrometry analysis. Among the ACS subjects, notable increases in the 22:6 LPA, 18:2 LPA, and 20:4 LPA levels were observed. The in vitro experiments revealed that serum incubation mainly increased the 18:2 LPA level, whereas platelet activation increased the 20:4 LPA level. Minor lysophospholipids other than LPA were also elevated in ACS subjects and were well correlated with the corresponding LPA species, including 22:6 LPA. A multiple regression analysis also revealed that lysophosphatidylinositol, lysophosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidylglycerol were independent explanatory variables for several LPA species. Conclusions-Specific LPA species, especially long-chain unsaturated LPA, were elevated in ACS patients, along with the corresponding minor lysophospholipids. The elevation of these LPA species might be mainly caused by presently unidentified LPA-producing pathway(s). Minor lysophospholipids might be involved in the generation of LPA, especially 22:6 LPA, and in the pathogenesis of ACS. LPA levels were elevated in patients with ACS but not in those with stable angina pectoris (SAP). 16 This result suggested that LPA might be involved in plaque instability and platelet activation in human subjects. In addition, we also found that serum autotaxin levels were not elevated in patients with ACS; LPA is hydrolyzed from lysophosphatidylcholine (LPC) by autotaxin/lysophospholipase D. 17 This discrepancy between LPA and autotaxin interested us greatly because autotaxin is a key enzyme in the production of LPA. Actually, we previously reported a strong positive correlation between LPA and autotaxin in healthy subjects, 18 patients with chronic hepatitis, 19 and patients with follicular lymphoma.20 Therefore, the discordance between ACS subjects and other subjects prompted us to investigate the origins of the elevation in LPA in patients with ACS.LPA is structurally composed of a fatty acid linked to snglycerol-3 phosphate, and the molecular species of the fatty acid chain are varied and determine the molecular species of LPA. In a previous report, 16 we measured the total LPA and LPC levels using previously described enzymatic methods. 21 Using these methods, we could not obtain any information concerning which molecular species of LPA were elevated in patients with ACS. To overcome this limitation, we determined th...

Objective. Lysophosphatidic acid (LPA) is a bioactive lipid that binds to a group of cell surface G protein-coupled receptors (LPA receptors 1-6 [LPA 1-6 ]) and has been implicated as an important mediator of angiogenesis, inflammation, and cancer growth. This study was undertaken to analyze the effects of LPA 1 on the development of arthritis.Methods. Expression of LPA receptors on synovial tissue was analyzed by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. The effects of abrogation of LPA 1 on collageninduced arthritis (CIA) were evaluated using LPA 1 -deficient mice or LPA 1 antagonist. Migrating fluorescence-labeled CD11b؉ splenocytes, which were transferred into the synovium of mice with CIA, were counted. CD4؉ naive T cells were incubated under Th1-, Th2-, or Th17-polarizing conditions, and T helper cell differentiation was assessed. Osteoclast formation from bone marrow cells was examined.Results. LPA 1 was highly expressed in the synovium of patients with rheumatoid arthritis (RA) compared with that of patients with osteoarthritis. LPA 1 -deficient mice did not develop arthritis following immunization with type II collagen (CII). LPA 1 antagonist also ameliorated murine CIA. Abrogation of LPA 1 was associated with reductions in cell infiltration, bone destruction in the joints, and interleukin-17 production from CII-stimulated splenocytes. Infiltration of transferred CD11b؉ macrophages from LPA 1 -deficient mice into the synovium was suppressed compared with infiltration of macrophages from wild-type mice. LPA 1 antagonist inhibited the infiltration of macrophages from wild-type mice. Differentiation into Th17, but not Th1 or Th2, and osteoclast formation were also suppressed under conditions of LPA 1 deficiency or LPA 1 inhibition in vitro.Conclusion. Collectively, these results indicate that LPA/LPA 1 signaling contributes to the development of arthritis via cellular infiltration, Th17 differentiation, and osteoclastogenesis. Thus, LPA 1 may be a promising target molecule for RA therapy.Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by inflammatory cell infiltration and bone destruction at multiple joints. The inflammation process in RA leads to synovial hyperplasia with proliferation of fibroblast-like synoviocytes (FLS), angiogenesis, and infiltration of inflammatory cells, including lymphocytes and macrophages (1,2).

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