Different origins of lysophospholipid mediators between coronary and peripheral arteries in acute coronary syndrome.

Lysophosphatidic acids (LysoPAs) and lysophosphatidylserine (LysoPS) are emerging lipid mediators proposed to be involved in the pathogenesis of acute coronary syndrome (ACS). In this study, we attempted to elucidate how LysoPA and LysoPS become elevated in ACS using human blood samples collected simultaneously from culprit coronary arteries and peripheral arteries in ACS subjects. We found that: 1) the plasma LysoPA, LysoPS, and lysophosphatidylglycerol levels were not different, while the lysophosphatidylcholine (LysoPC), lysophosphatidylinositol, and lysophosphatidylethanolamine (LysoPE) levels were significantly lower in the culprit coronary arteries; 2) the serum autotaxin (ATX) level was lower and the serum phosphatidylserine-specific phospholipase A1 (PS-PLA1) level was higher in the culprit coronary arteries; 3) the LysoPE and ATX levels were significant explanatory factors for the mainly elevated species of LysoPA, except for 22:6 LysoPA, in the peripheral arteries, while the LysoPC and LysoPE levels, but not the ATX level, were explanatory factors in the culprit coronary arteries; and 4) 18:0 and 18:1 LysoPS were significantly correlated with PS-PLA1 only in the culprit coronary arteries. In conclusion, the origins of LysoPA and LysoPS might differ between culprit coronary arteries and peripheral arteries, and substrates for ATX, such as LysoPC and LysoPE, might be important for the generation of LysoPA in ACS.

PLA1A2 platelet polymorphism predicts mortality in prediabetic subjects of the population based KORA S4-Cohort.

OBJECTIVE: The genetic polymorphism concerning the ß3-subunit of platelet integrin receptor glycoprotein IIIa is held responsible for enhanced binding of adhesive proteins resulting in increased thrombogenic potential. Whether it is associated with mortality, HbA1c or platelet volume is tested prospectively in an epidemiological cohort. RESEARCH DESIGN AND METHODS: Population-based Cooperative Health Research in the Region of Augsburg (KORA) S4-Survey (N = 4,028) was investigated for prognostic value of PLA1A2-polymorphism regarding all-cause mortality, correlation with HbA1c, and mean platelet volume. Multivariate analysis was performed to investigate association between genotype and key variables. RESULTS: Prevalence of thrombogenic allele variant PLA2 was 15.0%. Multivariate analysis revealed no association between PLA1A2 polymorphism and mortality in the KORA-cohort. HbA1c was a prognostic marker of mortality in non-diabetic persons resulting in J-shaped risk curve with dip at HbA1c = 5.5% (37 mmol/mol), confirming previous findings regarding aged KORA-S4 participants (55-75 years). PLA1A2 was significantly associated with elevated HbA1c levels in diabetic patients (N = 209) and reduced mean platelet volume in general population. In non-diabetic participants (N = 3,819), carriers of PLA2 allele variant presenting with HbA1c > 5.5% (37 mmol/mol) showed higher relative risk of mortality with increasing HbA1c. CONCLUSION: PLA1A2 polymorphism is associated with mortality in participants with HbA1c ranging from 5.5% (37 mmol/mol) to 6.5% (48 mmol/mol). Maintenance of euglycemic control and antiplatelet therapy are therefore regarded as effective primary prevention in this group.

Higher serum levels of autotaxin and phosphatidylserine-specific phospholipase A1 in patients with lupus nephritis.

BACKGROUND: Recent studies revealed that lysophospholipids (LPLs) and related molecules, such as autotaxin (ATX) and phosphatidylserine-specific phospholipase A1 (PS-PLA1 ), are candidates for novel biomarkers in melanoma, glaucoma and diabetic nephropathy. However, it is not clear whether serum levels of ATX/ PS-PLA1 would be associated with pathological and clinical findings of lupus nephritis (LN). METHODS: In this retrospective cohort study, serum samples were collected from 39 patients with LN and 37 patients with other glomerular diseases. The serum levels of ATX and PS-PLA1 were evaluated for an association with renal pathology and clinical phenotypes of LN. RESULTS: The serum levels of ATX and PS-PLA1 were higher in the patients with LN as compared to those with other glomerular diseases. Among the classes of LN, the patients with class IV showed the trend of lower serum levels of ATX. Moreover, the patients with lower levels of ATX exhibited higher scores of activity index (AI) and chronicity index (CI). The level of ATX tended to be negatively correlated with AI and CI. These results might be explained by the effect of treatment, because the serum levels of ATX and PS-PLA1 were inversely correlated with the daily amount of oral prednisolone. Moreover, they did not reflect the level of proteinuria or kidney survival in LN patients. CONCLUSION: Although the serum levels of ATX and PS-PLA1 were affected by the treatment, these levels were higher in the patients with LN. The potential clinical benefits of these markers need to be clarified in further studies.

Elevated phosphatidylserine-specific phospholipase A1 level in hyperthyroidism.

OBJECTIVES: Although a single nucleotide polymorphism in a specific receptor for lysophosphatidylserine, a lysophospholipid mediator involved in the immune system, is reportedly associated with Graves' disease, the association between lysophosphatidylserine and thyroid disorders remains to be elucidated. Therefore, we aimed to investigate the association between the level of phosphatidylserine-specific phospholipase A1 (PS-PLA1), which produces lysophosphatidylserine, and thyroid disorders. METHODS: We measured serum PS-PLA1 levels in the patients with various thyroid disorders (n = 120) and normal subjects (n = 58). RESULTS: We observed that the serum PS-PLA1 levels were higher in the subjects with Graves' disease, subacute thyroiditis, or silent thyroiditis, while they were not modulated in the patients with hypothyroidism. The serum PS-PLA1 levels were strongly correlated with the levels of thyroid hormones, especially in the subjects with Graves' disease. Moreover, we found that the serum PS-PLA1 levels were lowered by treatment with anti-thyroid reagents in subjects with Graves' disease and that the changes in PS-PLA1 were strongly correlated with those in thyroid hormones. CONCLUSION: These results suggest that PS-PLA1 might be a novel target in the treatment of hyperthyroidism, especially Graves' disease, and that its measurement might be useful as a supplementary diagnostic test for thyroid function.

Possible involvement of PS-PLA1 and lysophosphatidylserine receptor (LPS1) in hepatocellular carcinoma.

Lysophosphatidylserine (LysoPS) is a lysophospholipid, its generating enzyme, phosphatidylserine-specific phospholipase A1 (PS-PLA1), reportedly plays roles in stomach and colon cancers. Here, we examined the potential roles of LysoPS in hepatocellular carcinoma (HCC). The ninety-seven HCC patients who underwent surgical treatment were enrolled in this study and approved by the institutional review board. Among LysoPS-related enzymes and receptors, increased PS-PLA1 or LysoPS receptor 1 (LPS1) mRNA was observed in HCC tissues compared to non-HCC tissues. PS-PLA1 mRNA in HCC was associated with no clinical parameters, while LPS1 mRNA in HCC was correlated inversely with tumor differentiation. Furthermore, higher serum PS-PLA1 was observed in HCC patients compared to healthy control and correlated with PS-PLA1 mRNA in non-HCC tissues and with serum AST or ALT. Additionally, serum levels of PS-PLA1 were higher in HCC patients with HCV-related liver injury than in those with HBV or non-HBV-, non-HCV-related liver diseases. In conclusion, among LysoPS-related enzymes and receptors, PS-PLA1 and LPS1 mRNA were increased in HCC. Based on the correlation between the serum PS-PLA1 and the mRNA level of PS-PLA1 in non-HCC tissues, the liver may be the main source of serum PS-PLA1, and serum PS-PLA1 levels may be a useful marker for liver injury.

Serum phosphatidylserine-specific phospholipase A1 as a novel biomarker for monitoring systemic lupus erythematosus disease activity.

AIM: To assess the utility of serum levels of phosphatidylserine-specific phospholipase A1 (PS-PLA1 ), a lipase involved in the production of lysophosphatidylserine with multi-immunomodulatory effects, in systemic lupus erythematosus (SLE). METHOD: Serum PS-PLA1 was measured in 161 patients with SLE (including 54 untreated patients), 80 disease controls (35 active rheumatoid arthritis [RA], 23 Sjögren's syndrome [SS], and 22 systemic sclerosis [SSc]), and 237 healthy controls. RESULTS: Serum PS-PLA1 was significantly higher in SLE patients than in healthy controls, RA and SS patients. Although PS-PLA1 was significantly elevated in SSc and SS patients compared with healthy controls, PS-PLA1 was significantly higher in untreated SLE patients than in treated SLE patients and disease control patients. Receiver operating characteristic analysis revealed that a cut-off value of 18.2 ng/mL distinguished untreated SLE from disease control, with sensitivity and specificity of 71.4% and 57.5%, respectively. PS-PLA1 was significantly correlated with SLE Disease Activity Index (SLEDAI) and immunoglobulin G (IgG), and inversely correlated with white blood cell counts, lymphocyte counts, total complement hemolytic activity (CH50), complements C3, and C4 in SLE patients overall. Stepwise multiple regression identified SLEDAI, CH50, and IgG as significant parameters. In SLEDAI-based disease activity groups, PS-PLA1 was significantly higher in SLE patients with high disease activity than in those with low disease activity. PS-PLA1 decreased significantly in parallel with SLEDAI in 35 SLE patients whose paired serum samples were available pre- and post-treatment. CONCLUSION: Serum PS-PLA1 is associated with disease activity of SLE, indicating its possible use as a biomarker for monitoring SLE disease activity.

Association between serum autotaxin or phosphatidylserine-specific phospholipase A1 levels and melanoma.

Autotaxin (ATX), a producing enzyme for lysophosphatidic acids, was first identified from the medium of a melanoma cell line and has been considered to be one of the candidate targets to treat melanoma; however, the association between serum ATX and melanoma in human subjects has not been elucidated. Along with ATX, phosphatidylserine-specific phospholipase A1 (PS-PLA1 ) is a producing enzyme for lysophosphatidylserine, a similar glycero-lysophospholipid mediator to lysophosphatidic acids. In the present study, we aimed to investigate the association between serum ATX or PS-PLA1 levels and melanoma. We measured the serum levels of ATX, ATX isoforms and PS-PLA1 in subjects with melanoma (n = 57) and healthy subjects (n = 58). We further investigated the existence of trends according to the clinical stages of melanoma. We observed that serum total ATX and classical ATX levels were significant higher and serum novel ATX levels tended to be higher in male subjects with melanoma, while no significant difference was observed between the two groups in female subjects. The trend test revealed that the serum total ATX and ATX isoforms were significantly associated with the clinical stages of female subjects with melanoma. Regarding PS-PLA1 , serum PS-PLA1 levels were significantly higher in the melanoma subjects and associated with the clinical stages. The present study is the first study which revealed the association between ATX or PS-PLA1 and melanoma, suggesting the possible involvement of ATX/lysophosphatidic acids or PS-PLA1 /lysophosphatidylserine axis in the pathogenesis of melanoma.

Deletion of CaMKK2 from the liver lowers blood glucose and improves whole-body glucose tolerance in the mouse.

Ca(2+)/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a member of the Ca(2+)/CaM-dependent protein kinase family that is expressed abundantly in brain. Previous work has revealed that CaMKK2 knockout (CaMKK2 KO) mice eat less due to a central nervous system -signaling defect and are protected from diet-induced obesity, glucose intolerance, and insulin resistance. However, here we show that pair feeding of wild-type mice to match food consumption of CAMKK2 mice slows weight gain but fails to protect from diet-induced glucose intolerance, suggesting that other alterations in CaMKK2 KO mice are responsible for their improved glucose metabolism. CaMKK2 is shown to be expressed in liver and acute, specific reduction of the kinase in the liver of high-fat diet-fed CaMKK2(floxed) mice results in lowered blood glucose and improved glucose tolerance. Primary hepatocytes isolated from CaMKK2 KO mice produce less glucose and have decreased mRNA encoding peroxisome proliferator-activated receptor γ coactivator 1-α and the gluconeogenic enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, and these mRNA fail to respond specifically to the stimulatory effect of catecholamine in a cell-autonomous manner. The mechanism responsible for suppressed gene induction in CaMKK2 KO hepatocytes may involve diminished phosphorylation of histone deacetylase 5, an event necessary in some contexts for derepression of the peroxisome proliferator-activated receptor γ coactivator 1-α promoter. Hepatocytes from CaMKK2 KO mice also show increased rates of de novo lipogenesis and fat oxidation. The changes in fat metabolism observed correlate with steatotic liver and altered acyl carnitine metabolomic profiles in CaMKK2 KO mice. Collectively, these results are consistent with suppressed catecholamine-induced induction of gluconeogenic gene expression in CaMKK2 KO mice that leads to improved whole-body glucose homeostasis despite the presence of increased hepatic fat content.

A novel enzyme immunoassay for the determination of phosphatidylserine-specific phospholipase A(1) in human serum samples.

BACKGROUND: The bioactive lipid lysophosphatidylserine (LPS) is postulated to induce important biological responses and to be produced by phosphatidylserine-specific phospholipase A(1) (PS-PLA(1)). To evaluate the functional roles of LPS in vivo, a facile assay method for PS-PLA(1) has been awaited. METHODS: Recombinant human PS-PLA(1) was produced using a baculovirus system, and anti-human PS-PLA(1) monoclonal antibodies were generated. Two clones were then selected for a 2-site immunoassay. The resulting PS-PLA(1) assay reagent was applied to a commercial automated immunoassay analyzer. RESULTS: Satisfactory results were obtained for the within-run and between-run precision, interference, detection limit, and linearity of this PS-PLA(1) assay. The mean+/-SD of the serum PS-PLA(1) antigen concentration in the 191 healthy subjects was 33.8+/-16.6microg/l, and the central 95th percentile reference interval for the serum PS-PLA(1) antigen concentration was 13.8-74.1microg/l. The concentration was significantly (p<0.001) higher among men (13.8-80.6microg/l) than among women (12.1-68.8microg/l). We did not find a correlation between PS-PLA(1) and existing laboratory tests. CONCLUSIONS: The present PS-PLA(1) assay method can be applied to clinical laboratory testing, and further studies are warranted to establish its clinical significance.

Usefulness of self-reported periodontal disease to identify individuals with elevated inflammatory markers at risk of cardiovascular disease.

Periodontal disease has been associated with cardiovascular disease (CVD), and inflammation may represent a common pathophysiology. Oral health screening in the context of CVD risk assessment represents a potential opportunity to identify individuals at risk for CVD. The purposes of this study were to determine if self-reported oral health status is independently associated with inflammatory markers and if oral health assessment as part of CVD risk screening can identify at-risk individuals without traditional CVD risk factors. A baseline analysis was conducted among participants in the National Heart, Lung, and Blood Institute's Family Intervention Trial for Heart Health (FIT Heart; n = 421, mean age 48 +/- 13.5 years, 36% nonwhite) without CVD or diabetes who underwent standardized assessment of oral health, lifestyle, CVD risk factors, and the inflammatory markers high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A(2). Statistical associations between oral health, risk factors, and inflammatory markers were assessed, and logistic regression was used to adjust for effects of lifestyle and potential confounders. Periodontal disease was independently associated with being in the top quartile of lipoprotein-associated phospholipase A(2) compared with the lower 3 quartiles (odds ratio 1.9, 95% confidence interval 1.1 to 3.2) after adjustment for lifestyle and risk factors. Histories of periodontal disease were reported by 24% of non-overweight, non-hypertensive, non-hypercholesterolemic participants, and of these participants, 37% had elevated high-sensitivity C-reactive protein (> or =3 mg/L) or lipoprotein-associated phospholipase A(2) (> or =215 ng/ml) levels. In conclusion, self-reported periodontal disease is independently associated with inflammation and common in individuals without traditional CVD risk factors.