Group IIA Secretory Phospholipase A2 Research Articles

Oleanolic acid protects against cognitive decline and neuroinflammation-mediated neurotoxicity by blocking secretory phospholipase A2 IIA-activated calcium signals

Neuroinflammation causes neurotoxic injury and underlies the pathogenesis of neurodegenerative disorders including Alzheimer's disease (AD). Astrocytes are the predominant immunoregulatory cells in AD. Oleanolic acid (OA) is a promising anti-inflammatory therapeutic agent that can ameliorate cerebral damage in ischemic environments, but its role in AD remains poorly elucidated. Here, preconditioning with OA inhibited the transcription and secretion of inflammatory cytokines IL-6, TNF-α, and IL-1β in amyloid-beta peptide (Aβ)-activated astrocytes. Moreover, OA ameliorated primary neuron death triggered by incubation in conditioned medium from Aβ-treated astrocytes. Furthermore, OA also suppressed Aβ-induced expression and production of group IIA secretory phospholipase A2 (sPLA2-IIA) in astrocytes. Supernatants supplemented with exogenous sPLA2-IIA reversed the protective role of OA against astrocyte activation-mediated neurotoxicity by suppressing cell viability and increasing LDH release, apoptosis, the contents of neurotoxic mediator arachidonic acid, and prostaglandin D2. Simultaneously, treatment with sPLA2 inhibitor aristolochic acid also counteracted neurotoxicity induced by Aβ-activated astrocytes through increasing cell viability, inhibiting cell apoptosis, and reducing the releases of arachidonic acid and prostaglandin D2. Additionally, OA restrained Ca2+ influx in neurons after incubation with supernatants from Aβ-activated astrocytes, which was abrogated by adding sPLA2-IIA. Activating Ca2+ signaling with BayK, an L-type Ca2 + channel agonist, reversed the beneficial role of OA against neurotoxicity induced by astrocyte activation-mediated inflammatory response. OA also ameliorated cognitive deficits in an adolescent rat model of Aβ-evoked AD. These findings confirm that OA abrogates neuroinflammation and subsequent neurotoxicity induced by conditioned media from Aβ-activated astrocytes in sPLA2-IIA mediated-calcium signals. Therefore, OA may protect neurons from injury caused by neighboring astrocyte activation in AD, indicating a promising therapeutic strategy against AD.

Effect of Tumor Conditioned Media from Prostate Cancer Cells on Fibroblast Cell Morphology, Viability and Gene Expression

Cancer is a heterogeneous collection of neoplastic cells, surrounded by non‐malignant, stromal cells, and extracellular matrix (ECM), among other constituents. Cross‐talk between tumor and stromal cells forms a dynamic tumor microenvironment (TME) that mediates cell growth, proliferation, and metastasis. The TME can act to inhibit cancer growth and proliferation during the initial stages of carcinogenesis. However, cancer cells are able to evade these inhibitory signals, and subsequently reshape the TME, making it more amenable to their own growth. This gives rise to numerous cancer‐associated stromal cells, including cancer‐associated fibroblasts (CAFs). CAFs further modulate the TME by regulating the release of growth signals, cell death, ECM remodeling, angiogenesis, and epithelial‐mesenchymal transition. To study the ability of prostate cancer to alter the TME in vitro, we exposed human bone fibroblasts (HS‐5 cells) to tumor conditioned media isolated from a human neuroendocrine prostate cancer cell line (DU145) and assessed changes in cell morphology, viability (using MTT assay) and the expression of Group IIA secretory phospholipase A2 (PLA2G2A), as well as its regulatory proteins, glypican‐1 (GPC‐1) and Group IVA phospholipase A2 (PLA2G4A), using qPCR. Exposure of HS‐5 cells to TCM from DU145 cells altered cellular morphology to a more mesenchymal phenotype typically seen in active myofibroblasts. TCM also decreased MTT staining in a time‐dependent manner that was independent of the presence of serum in the TCM. Changes in cell morphology and viability correlated to increases in the expression of PLA2G2A, GPC‐1 and PLA2G4A. The effect of TCM was time‐ and serum‐dependent, and was differential for each gene studied. Alteration in cellular morphology and increases in PLA2G2A, GPC‐1 and PLA2G4A in HS‐5 cells correlated to increases in the expression of fibroblast activation protein‐α, which is a CAF marker. To elucidate the mechanisms mediating changes in HS‐5 cells exposed to TCM, we investigated the expression of GLi1, a transcription factor involved in the activation of the sonic hedgehog signaling pathway. We found that TCM increased GLi1 mRNA levels in HS‐5 cells, with greater increases being observed using TCM containing serum. Collectively, these data demonstrate that media from DU145 cells can induce morphological and genotypic changes in human fibroblasts similar to those observed in CAFs. As such, this model holds promise for identifying molecular mechanisms by which prostate cancer cells alter the TME and induce prostate cancer cell growth.Support or Funding InformationNational Institute of Biomedical Imaging and Bioengineering NIBIB (EB0160100)Department of Defense Prostate Cancer Research Program Idea Development Award (PC150431 GRANT11996600)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Measurement of a Novel Biomarker, Secretory Phospholipase A2 Group IIA as a Marker of Sepsis: A Pilot Study.

Introduction:Early identification of sepsis is critical as early treatment improves outcomes. We sought to identify threshold values of secretory phospholipase A2 (sPLA2)-IIA that predict sepsis and bacterial infection compared to nonseptic controls in an emergency department (ED) population.Materials and Methods:This is a prospective cohort of consenting adult patients who met two or more systemic inflammatory response syndrome (SIRS) criteria with clinical diagnosis of infectious source likely (septic patients). Controls were nonseptic consenting adults undergoing blood draw for other ED indications. Both groups had blood drawn, blind-coded, and sent to an outside laboratory for quantitative analysis of sPLA2-IIA levels. The study investigators reviewed patients’ inpatient medical record for laboratory, imaging, and microbiology results, as well as clinical course.Results:sPLA2-IIA levels were significantly lower in control patients as compared to septic patients (median = 0 ng/ml [interquartile range (IQR): 0–6.5] versus median = 123 ng/ml [IQR 44–507.75]; P < 0.0001). SPLA2-IIA levels were higher in patients with confirmed source (n = 28 patients, median = 186 ng/ml, 95% confidence interval = 115.1–516.8) as compared to those with no source identified or a viral source (n = 17, median = 68 ng/ml, 95% confidence interval = 38.1–122.7; P = 0.04). Using a cutoff value of 25 ng/ml, sPLA2-IIA had a sensitivity of 86.7% (confidence interval 72.5–94.5) and a specificity of 91.1% (confidence interval 77.9–97.1) in detecting sepsis.Conclusions:sPLA2-IIA shows potential as a biomarker distinguishing sepsis from other disease entities. Further study is warranted to identify predictive value of trends in sPLA-IIA during disease course in septic patients.

The need for Group IIA secretory phospholipase A2 (sPLA2-IIA) inhibitors in inflammatory ocular disease treatment

The need for Group IIA secretory phospholipase A2 (sPLA2-IIA) inhibitors in inflammatory ocular disease treatment

A Concise Update on the Relevance of Secretory Phospholipase A2 Group IIA and its Inhibitors with Cancer.

Secretory phospholipase A2 group IIA (sPLA2-IIA) is an enzyme that hydrolyzes the sn-2 ester bond in glyceroacyl phospholipids present in lipoproteins and cell membranes. As many immunohistochemical studies reveal that the high expression of sPLA2-IIA in the tumorous tissue or plasma of cancer patients, though low expression in other cases, the enzyme is considered highly relevant with cancer development. Effort has been made to establish the mechanism of how sPLA2- IIA is involved in various cancers in order to understand its pathogenic role and to utilize it as a target for cancer diagnosis and therapy. This article specifically reviews recent studies regarding the relevance of sPLA2-IIA with various cancers and reported inhibitors of the protein.

Secretory phospholipase A2-IIA overexpressing mice exhibit cyclic alopecia mediated through aberrant hair shaft differentiation and impaired wound healing response

Secretory phospholipase A2 Group-IIA (sPLA2-IIA) is involved in lipid catabolism and growth promoting activity. sPLA2-IIA is deregulated in many pathological conditions including various cancers. Here, we have studied the role of sPLA2-IIA in the development of cyclic alopecia and wound healing response in relation to complete loss of hair follicle stem cells (HFSCs). Our data showed that overexpression of sPLA2-IIA in homozygous mice results in hyperproliferation and terminal epidermal differentiation followed by hair follicle cycle being halted at anagen like stage. In addition, sPLA2-IIA induced hyperproliferation leads to complete exhaustion of hair follicle stem cell pool at PD28 (Postnatal day). Importantly, sPLA2-IIA overexpression affects the hair shaft differentiation leading to development of cyclic alopecia. Molecular investigation study showed aberrant expression of Sox21, Msx2 and signalling modulators necessary for proper differentiation of inner root sheath (IRS) and hair shaft formation. Further, full-thickness skin wounding on dorsal skin of K14-sPLA2-IIA homozygous mice displayed impaired initial healing response. Our results showed the involvement of sPLA2-IIA in regulation of matrix cells differentiation, hair shaft formation and complete loss of HFSCs mediated impaired wound healing response. These novel functions of sPLA2-IIA may have clinical implications in alopecia, cancer development and ageing.

Secretory phospholipase A2 group IIA modulates insulin sensitivity and metabolism

Secretory phospholipase A2 group IIA (PLA2G2A) is a member of a family of secretory phospholipases that have been implicated in inflammation, atherogenesis, and antibacterial actions. Here, we evaluated the role of PLA2G2A in the metabolic response to a high fat diet. C57BL/6 (BL/6) mice do not express PLA2g2a due to a frameshift mutation. We fed BL/6 mice expressing the human PLA2G2A gene (IIA+ mice) a fat diet and assessed the physiologic response. After 10 weeks on the high fat diet, the BL/6 mice were obese, but the IIA+ mice did not gain weight or accumulate lipid. The lean mass in chow- and high fat-fed IIA+ mice was constant and similar to the BL/6 mice on a chow diet. Surprisingly, the IIA+ mice had an elevated metabolic rate, which was not due to differences in physical activity. The IIA+ mice were more insulin sensitive and glucose tolerant than the BL/6 mice, even when the IIA+ mice were provided the high fat diet. The IIA+ mice had increased expression of uncoupling protein 1 (UCP1), sirtuin 1 (SIRT1), and PPARγ coactivator 1α (PGC-1α) in brown adipose tissue (BAT), suggesting that PLA2G2A activates mitochondrial uncoupling in BAT. Our data indicate that PLA2G2A has a previously undiscovered impact on insulin sensitivity and metabolism.

The role of group IIA secretory phospholipase A2 (sPLA2-IIA) as a biomarker for the diagnosis of sepsis and bacterial infection in adults-A systematic review.

IntroductionThis paper investigates the role of Group II Secretory Phospholipase A2 (sPLA2-IIA) as a biomarker for the diagnosis of sepsis and bacterial infection in adults. Sepsis and bacterial infection are common problems encountered by patients in the hospital and often carry adverse outcomes if not managed early.MethodsTwo independent reviewers conducted a comprehensive search using Ovid MEDLINE published from years 1993 to 2016 and SCOPUS published from year 1985 to 2017 to screen for relevant studies. The main inclusion criteria included adult subjects, patients with suspected or confirmed signs of infection and relevant outcomes which looked into the role of sPLA2-IIA in detecting the presence of sepsis and bacterial infection in the subjects.Results and discussionFour studies met the inclusion criteria. SPLA2-IIA was found to be effective in detecting the presence of sepsis and bacterial infection in adults. The levels of serum sPLA2-IIA also correlated well with the presence of sepsis and bacterial infection.ConclusionThis systematic review highlights the role of sPLA2-IIA as a reliable tool to diagnose sepsis and bacterial infection in adult patients. Nonetheless, further studies should be done in the future to provide more compelling evidence on its application in the clinical setting.

Inhibitory Effect of Zingerone on Secretory Group IIA Phospholipase A2

The expression of secretory group IIA phospholipase A2 (sPLA2-IIA) has been shown to be elevated in various inflammatory diseases, and lipopolysaccharide (LPS) up-regulates the expression of sPLA2-IIA in human umbilical vein endothelial cells (HUVECs). Zingerone (ZGR), a phenolic alkanone isolated from ginger, has been reported to have various pharmacological activities. Here, we examined the effects of ZRG on the expression and activity of sPLA2-IIA in LPS-activated HUVECs and in mouse models of endotoxemia and sepsis. Treatment of cells or mice with ZRG inhibited LPS-induced expression and activity of sPLA2-IIA. In addition, ZRG suppressed LPS-mediated activation of cytosolic phospholipase A2 (cPLA2) and extracellular signal-regulated kinase (ERK) 1/2. These results suggest that ZRG inhibits LPS-mediated activation of sPLA2-IIA expression by suppressing cPLA2 and ERK 1/2.

Overexpression of secretory phospholipase A2-IIa supports cancer stem cell phenotype via HER/ERBB-elicited signaling in lung and prostate cancer cells.

Resistance to conventional chemotherapies remains a significant clinical challenge in treatment of cancer. The cancer stem cells (CSCs) have properties necessary for tumor initiation, resistance to therapy, and progression. HER/ERBB‑elicited signaling supports CSC properties. Our previous studies revealed that secretory phospholipaseA2 groupIIa (sPLA2‑IIa) is overexpressed in both prostate and lung cancer cells, leading to an aberrant high level in the interstitial fluid, i.e.,tumor microenvironment and blood. HER/ERBB-PI3K-Akt-NF-κB signaling stimulates sPLA2‑IIa overexpression, and in turn, sPLA2‑IIa activates EGFR family receptors and HER/ERBB-elicited signaling and stimulates sPLA2‑IIa overexpression in a positive feedback manner. The present study determined the molecular mechanisms of sPLA2‑IIa in stimulating HER/ERBB-elicited signaling and supporting CSC properties. We found that sPLA2‑IIa binds both EGFR and HER3 demonstrated by co-immunoprecipitation experiments and also indirectly interacts with HER2, suggesting that sPLA2‑IIa functions as a ligand for both EGFR and HER3. Furthermore, both side population CSCs from non-small cell lung cancer (NSCLC) A549 and H1975 cells and ALDH1‑high CSCs from castration-resistant prostate cancer (CRPC) 22Rv1 cells overexpress sPLA2‑IIa and produce tumors when inoculated into subcutis of nude mice. Given an aberrant high level of sPLA2‑IIa in the tumor microenvironment that should be much higher than that in the blood, our findings support the notion that sPLA2‑IIa functions as a ligand for EGFR family receptors and supports CSC properties via HER/ERBB-elicited signaling, which may contribute to resistance to therapy and cancer progression.

Celastrol modulates inflammation through inhibition of the catalytic activity of mediators of arachidonic acid pathway: Secretory phospholipase A2 group IIA, 5-lipoxygenase and cyclooxygenase-2

Elevated production of arachidonic acid (AA)-derived pro-inflammatory eicosanoids due to the concerted action of secretory phospholipase A2 group IIA (sPLA2IIA), 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) is a common feature of many inflammatory disorders. Hence, modulation of the bioactivity of these 3 enzymes is an important strategy to control inflammation. However, the failure of drugs specific for an individual enzyme (sPLA2IIA-, 5-LOX- or COX-2) and the success of 5-LOX/COX-2 dual inhibitors in effectively controlling inflammation in clinical trials prompted us to evaluate a common inhibitor for sPLA2IIA, 5-LOX and COX-2 enzymes. Celastrol, a quinone methide triterpene, was selected in this regard through molecular docking studies. We provide the first evidence for celastrol’s ability to inhibit the catalytic activity of sPLA2IIA, 5-LOX and COX-2 enzymes. Celastrol significantly inhibited the catalytic activity of sPLA2IIA (IC50=6μM) in vitro, which is independent of substrate and calcium concentration. In addition, celastrol inhibited the catalytic activities of 5-LOX (IC50=5μM) and COX-2 (IC50=20μM) in vitro; sPLA2IIA-induced edema and carrageenan-induced edema in mice; and lipopolysaccharide-stimulated production of PGE2 in human neutrophils. Thus, celastrol modulates inflammatory responses by targeting multiple enzymes of AA pathway.

Inhibitory Effect of Three Diketopiperazines from Marine-derived Bacteria on Secretory Group IIA Phospholipase A2

Diketopiperazines, natural products found in bacteria, fungi, marine sponges, gorgonian and red algae, are cyclic dipeptides possessing relatively-simple and rigid structures with chiral nature and various side chains. The compounds in this structure class have been known to possess diverse bioactivities including antibiotic activity, anti-cancer activity, neuroprotective activity, and anti-inflammatory activity. The expression of secretory group IIA phospholipase A2 (sPLA2-IIA) is enhanced by development of inflammatory disorders. Aim of this study is to determine the effects of diketopiperazines on the secretion and activity of sPLA2-IIA by lipopolysaccharide (LPS) in human umbilical vein endothelial cells (HUVECs). To do this, sPLA2-IIA expression was induced in the LPS-stimulated HUVECs and mice to evaluate the effect of diketopiperazines. Results showed that diketopiperazines remarkably suppressed the LPS-mediated protein expression and activity of sPLA2-IIA via inhibition of phosphorylation of cytosolic phospholipase A2 (cPLA2) and extracellular signal-regulated kinase (ERK) 1/2. These results demonstrated that diketopiperazines might play an important role in the modulation of sPLA2-IIA expression and activity in response to the inflammatory diseases.

Dabrafenib, as a Novel Insight into Drug Repositioning Against Secretory Group IIa Phospholipase A2

Dabrafenib, as a Novel Insight into Drug Repositioning Against Secretory Group IIa Phospholipase A2

Abstract 326: Group IIA Secretory Phospholipase A 2 Predicts Graft Failure and Cardiovascular Mortality in Renal Transplant Recipients by Mediating Decreased Kidney Function

The acute phase protein group IIA secretory phospholipase A2 (sPLA2-IIA) has proatherosclerotic properties. The present study prospectively investigated whether plasma sPLA2-IIA levels are associated with graft failure, cardiovascular and all-cause mortality in renal transplant recipients (RTRs), patients known to be susceptible to accelerated atherosclerosis, both in the graft and in the systemic vasculature. In 495 RTRs (median follow-up 7.0 years) sPLA2-IIA was determined at baseline and was significantly higher in RTRs than in healthy controls (median 384 ng/dL [range 86-6951] vs. 185 ng/dL [range 104-271], P&lt;0.001), but lower than in end-stage renal disease patients (median 1053 ng/mL [range 458-2599], P&lt;0.001). Kaplan-Meier analysis demonstrated an increased risk for graft failure (P=0.002), cardiovascular (P&lt;0.001) and all-cause mortality (P&lt;0.001) with increasing gender-stratified quartiles of sPLA2-IIA. Cox regression analyses showed a strong association of sPLA2-IIA with increased risks of graft failure (hazard ratio=1.42[1.11-1.83], P=0.006), cardiovascular (hazard ratio=1.48[1.18-1.85], P=0.001) and all-cause mortality (hazard ratio=1.39[1.17-1.64], P&lt;0.001). However, this association was largely explained by parameters of kidney function. Further analyses in RTRs demonstrated that patients with higher baseline sPLA2-IIA levels showed faster decline in renal function during follow-up. In addition, kidney function in human sPLA2-IIA transgenic mice deteriorated more rapid over time as compared with wild-type controls (urinary albumin:creatinine ratio at 48 weeks of age 774±156 vs. 193±60, P&lt;0.01). In summary, this prospective study demonstrates that sPLA2-IIA is a significant predictive biomarker for the occurrence of chronic graft failure, overall and CVD mortality in RTRs dependent on kidney function. This dependency is explained by sPLA2-IIA impacting negatively on kidney function over time in humans and transgenic mice.

Dimethyl ester of bilirubin exhibits anti-inflammatory activity through inhibition of secretory phospholipase A2, lipoxygenase and cyclooxygenase

Overproduction of arachidonic acid (AA) mediated by secretory phospholipase A2 group IIA (sPLA2IIA) is a hallmark of many inflammatory disorders. AA is subsequently converted into pro-inflammatory eicosanoids through 5-lipoxygenase (5-LOX) and cyclooxygenase-1/2 (COX-1/2) activities. Hence, inhibition of sPLA2IIA, 5-LOX and COX-1/2 activities is critical in regulating inflammation. We have previously reported unconjugated bilirubin (UCB), an endogenous antioxidant, as sPLA2IIA inhibitor. However, lipophilic UCB gets conjugated in liver with glucuronic acid into hydrophilic conjugated bilirubin (CB). Since hydrophobicity is pre-requisite for sPLA2IIA inhibition, conjugation reduces the efficacy of UCB. In this regard, UCB was chemically modified and derivatives were evaluated for sPLA2IIA, 5-LOX and COX-1/2 inhibition. Among the derivatives, BD1 (dimethyl ester of bilirubin) exhibited ∼ 3 fold greater inhibitory potency towards sPLA2IIA compared to UCB. Both UCB and BD1 inhibited human 5-LOX and COX-2 activities; however only BD1 inhibited AA induced platelet aggregation. Molecular docking studies demonstrated BD1 as better inhibitor of aforesaid enzymes than UCB and other endogenous antioxidants. These data suggest that BD1 exhibits strong anti-inflammatory activity through inhibition of AA cascade enzymes which is of great therapeutic importance.

Development of a potent 2-oxoamide inhibitor of secreted phospholipase A2 guided by molecular docking calculations and molecular dynamics simulations

Inhibition of group IIA secreted phospholipase A2 (GIIA sPLA2) has been an important objective for medicinal chemists. We have previously shown that inhibitors incorporating the 2-oxoamide functionality may inhibit human and mouse GIIA sPLA2s. Herein, the development of new potent inhibitors by molecular docking calculations using the structure of the known inhibitor 7 as scaffold, are described. Synthesis and biological evaluation of the new compounds revealed that the long chain 2-oxoamide based on (S)-valine GK241 led to improved activity (IC50=143nM and 68nM against human and mouse GIIA sPLA2, respectively). In addition, molecular dynamics simulations were employed to shed light on GK241 potent and selective inhibitory activity.

Point of care testing of phospholipase A2 group IIA for serological diagnosis of rheumatoid arthritis

Secretory phospholipase A2 group IIA (sPLA2-IIA) was examined as a point of care marker for determining disease activity in rheumatoid (RA) and psoriatic (PsA) arthritis. Serum concentration and activity of sPLA2-IIA were measured using in-house antibodies and a novel point of care lateral flow device assay in patients diagnosed with varying severities of RA (n = 30) and PsA (n = 25) and found to correlate strongly with C-reactive protein (CRP). Levels of all markers were elevated in patients with active RA over those with inactive RA as well as both active and inactive PsA, indicating that sPLA2-IIA can be used as an analogue to CRP for RA diagnosis at point of care.

Inhibitory effect of polyozellin on secretory group IIA phospholipase A2.

The expression of secretory group IIA phospholipase A2 (sPLA2-IIA) is enhanced by development of inflammatory disorders. In this study, sPLA2-IIA expression was induced in the lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells and mice to evaluate the effect of polyozellin. Polyozellin, a major constituent of a Korea edible mushroom Polyozellus multiplex, has been known to exhibit the biological activities such as anti-oxidative and anti-inflammatory effects. Polyozellin remarkably suppressed the LPS-mediated protein expression and activity of sPLA2-IIA via inhibition of phosphorylation of cytosolic phospholipase A2 and extracellular signal-regulated kinase 1/2. These results demonstrated that polyozellin might play an important role in the modulation of sPLA2-IIA expression and activity in response to the inflammatory diseases.

Abstract 18502: Mass and Genetic Polymorphism of Group IIA Secretory Phospholipase A2, Rosuvastatin Therapy, and Risk of Cardiovascular Events: An Analysis From the JUPITER Trial

Background: Although group IIA secretory phospholipase A2 (sPLA2-IIA) is well appraised for its involvement in atherosclerosis by modifying LDL, its role in managing CVD risk in a primary prevention setting with low LDL-C is unknown. Furthermore, the utility of sPLA2-IIA mass for assessing future CVD risk relative to statin therapy in a population free of CVD is unknown. Methods: We analyzed data from JUPITER (NCT00239681) in which participants with LDL cholesterol &lt;130 mg/dL and hsCRP≥2 mg/L were randomized to rosuvastatin 20mg/day vs placebo. sPLA2-IIA was quantified by sandwich-type ELISA (Cayman) in 11269 participants before and 1 year after randomization. Cox regression was used to examine the association of sPLA2-IIA with CVD. The impact of lifelong reduction in sPLA2-IIA on CVD risk was assessed by Mendelian randomization analysis in 6692 participants. Results: 313 first CVD events occurred during maximum follow-up of 5.0 (median, 1.9) years. Baseline sPLA2-IIA levels (median, 25th-75th percentile: 3.81, 2.49-6.03 ng/ml) were associated with increased risk of CVD: after adjusting for age, sex, race, treatment, smoking, family history, BMI, blood pressure, glucose, HDL-C, LDL-C, and triglycerides, HR (95%CI, p-value) per SD in sPLA2-IIA was 1.22 (1.08-1.38; p= 0.002). This association was slightly attenuated after additionally adjusting for hsCRP (1.18, 1.04-1.35; p=0.01) and there was no statistical heterogeneity by rosuvastatin therapy. In the rosuvastatin arm, on-treatment sPLA2-IIA levels trended towards an increased residual risk of CVD; HR 1.19 (0.97-1.45; p=0.09) in multivariable adjusted model, this was attenuated after additionally adjusting for hsCRP (HR: 1.08 95% CI 0.87-1.34; p=0.50). rs11573156C in PLA2G2A (encoding sPLA2-IIA) had the strongest effect on sPLA2-IIA levels, median (25th-75th percentile) for the CC and GG genotype were 2.79 (1.97-4.01 ng/mL) and 7.38 (5.38-10.19 ng/mL), respectively; but showed a non-significant association with CVD risk (HR: 1.11, 95% CI 0.89-1.38, p=0.34). Conclusion: While sPLA2-IIA may be a measurable biomarker to assess the prognostic impact of inflammation on baseline and residual CVD risk, this result do not support sPLA2-IIA as a viable pharmacological target for reducing CVD risk.

Expression of secreted phospholipase A2-Group IIA correlates with prognosis of gastric adenocarcinoma.

The present study investigated the expression of secretory phospholipase A2-Group IIA (sPLA2-II) in gastric adenocarcinoma, in order to evaluate the correlation between sPLA2-II expression, and the clinicopathological features and prognosis of patients with gastric adenocarcinoma. Between January 2007 and April 2010, data were collected from 65 patients (44 males, 21 females; age range, 30-79 years; mean 66.7 ± 10.7 years). All patients exhibited a pathologically confirmed diagnosis of gastric adenocarcinoma. Endoscopic biopsy specimens of normal gastric mucosa from 11 of these patients were used as controls. Patients were subsequently followed-up at 3-month intervals, and survival data were recorded until April 2010. Expression of sPLA2-II in 65 gastric adenocarcinoma and 11 normal gastric mucosa specimens was evaluated via immunohistochemistry. A semi-quantitative method, consisting of evaluation of staining percentage and intensity, was utilized for immunohistochemical scoring, and the receiver operating characteristic curve method was applied to select a cut-off score for high and low sPLA2-II expression. The value of 8 was selected as the cut-off score, with maximum sensitivity and specificity. High sPLA2-II expression was observed in stage III/IV cases (83.3%; 40/48) and poorly differentiated cells (94.1%; 32/34), while sPLA2-II expression levels were observed to be significantly lower in stage I/II cases (52.9%; 9/17) and well and moderately differentiated cells (54.8%; 17/31; P=0.021 and P<0.001, respectively). There were no significant correlations observed between sPLA2-II expression and any other clinicopathological parameters, including gender, age, tumor diameter and Helicobacter pylori infection. Patients exhibiting low sPLA2-II expression experienced significantly improved overall survival (OS) and disease-free survival (DFS), compared with those exhibiting high sPLA2-II expression (P=0.043 and P=0.035, respectively). Multivariate analysis confirmed that high sPLA2-II expression may be an independent prognostic factor for OS [relative risk, 2.849; 95% confidence interval (CI), 1.088-7.459; P=0.033] and DFS (relative risk, 2.735; 95% CI, 1.104-6.776; P=0.030) in gastric adenocarcinoma. Therefore, sPLA2-II may be correlated with the histogenesis of gastric adenocarcinoma, and increased sPLA2-II expression may be an indicator of poor prognosis.