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Group IIA Secretory Phospholipase A2 Predicts Graft Failure and Mortality in Renal Transplant Recipients by Mediating Decreased Kidney Function.

ABSTRACT: The acute phase protein group IIA secretory phospholipase A2 (sPLA2-IIA) has intrinsic proatherosclerotic properties. The present prospective cohort study investigated whether plasma sPLA2-IIA associates with graft failure, cardiovascular, and all-cause mortality in renal transplant recipients (RTRs), patients with accelerated atherosclerosis formation both systemically and within the graft. In 511 RTRs from a single academic center with stable graft function >1 year, baseline plasma sPLA2-IIA was determined by ELISA. Primary end points were death-censored graft failure and mortality (median follow-up, 7.0 years). Baseline sPLA2-IIA was higher in RTRs than in healthy controls (median 384 ng/dL (range 86-6951) vs. 185 ng/dL (range 104-271), p < 0.001). Kaplan-Meier analysis demonstrated increased risk for graft failure (p = 0.002), as well as cardiovascular (p < 0.001) and all-cause mortality (p < 0.001), with increasing sPLA2-IIA quartiles. Cox regression showed strong associations of sPLA2-IIA with increased risks of graft failure (hazard ratio (HR) = 1.42 (1.11-1.83), p = 0.006), as well as cardiovascular (HR = 1.48 (1.18-1.85), p = 0.001) and all-cause mortality (HR = 1.39 (1.17-1.64), p < 0.001), dependent on parameters of kidney function. Renal function during follow-up declined faster in RTRs with higher baseline sPLA2-IIA levels. In RTRs, sPLA2-IIA is a significant predictive biomarker for chronic graft failure, as well as overall and cardiovascular disease mortality dependent on kidney function. This dependency is conceivably explained by sPLA2-IIA impacting negatively on kidney function.

SUBMITTER: Annema W

PROVIDER: S-EPMC7288094 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Functional analysis of two PLA2G2A variants associated with secretory phospholipase A2-IIA levels.

Project description:BackgroundSecretory phospholipase A2 group IIA (sPLA2-IIA) has been identified as a biomarker of atherosclerosis in observational and animal studies. The protein is encoded by the PLA2G2A gene and the aim of this study was to test the functionality of two PLA2G2A non-coding SNPs, rs11573156 C>G and rs3767221 T>G where the rare alleles have been previously associated with higher and lower sPLA2-IIA levels respectively.Methodology/principal findingsLuciferase assays, electrophoretic mobility shift assays (EMSA), and RNA expression by RT-PCR were used to examine allelic differences. For rs3767221 the G allele showed ∼55% lower luciferase activity compared to the T allele (T = 62.1 (95% CI 59.1 to 65.1) G = 27.8 (95% CI 25.0 to 30.6), p = 1.22×10⁻³⁵, and stronger EMSA binding of a nuclear protein compared to the T-allele. For rs11573156 C >G there were no luciferase or EMSA allelic differences seen. In lymphocyte cell RNA, from individuals of known rs11573156 genotype, there was no allelic RNA expression difference for exons 5 and 6, but G allele carriers (n = 7) showed a trend to lower exon 1-2 expression compared to CC individuals. To take this further, in the ASAP study (n = 223), an rs11573156 proxy (r² = 0.91) showed ∼25% higher liver expression of PLA2G2A (1.67×10⁻¹⁷) associated with the G allele. However, considering exon specific expression, the association was greatly reduced for exon 2 (4.5×10⁻⁵) compared to exons 3-6 (10⁻¹⁰ to 10⁻²⁰), suggesting rs11573156 G allele-specific exon 2 skipping.ConclusionBoth SNPs are functional and provide useful tools for Mendelian Randomisation to determine whether the relationship between sPLA2-IIA and coronary heart disease is causal.

| S-EPMC3412631 | biostudies-literature

HDL Cholesterol Efflux Predicts Graft Failure in Renal Transplant Recipients.

Project description:High-density lipoprotein (HDL) particles are involved in the protection against cardiovascular disease by promoting cholesterol efflux, in which accumulated cholesterol is removed from macrophage foam cells. We investigated whether HDL cholesterol efflux capacity is associated with cardiovascular mortality, all-cause mortality, and graft failure in a cohort of renal transplant recipients (n=495, median follow-up 7.0 years). Cholesterol efflux capacity at baseline was quantified using incubation of human macrophage foam cells with apolipoprotein B-depleted plasma. Baseline efflux capacity was not different in deceased patients and survivors (P=0.60 or P=0.50 for cardiovascular or all-cause mortality, respectively), whereas recipients developing graft failure had lower efflux capacity than those with functioning grafts (P<0.001). Kaplan-Meier analysis demonstrated a lower risk for graft failure (P=0.004) but not cardiovascular (P=0.30) or all-cause mortality (P=0.31) with increasing gender-stratified tertiles of efflux capacity. Cox regression analyses adjusted for age and gender showed that efflux capacity was not associated with cardiovascular mortality (hazard ratio [HR], 0.89; 95% confidence interval [95% CI], 0.67 to 1.19; P=0.43). Furthermore, the association between efflux capacity and all-cause mortality (HR, .79; 95% CI, 0.63 to 0.98; P=0.031) disappeared after further adjustment for potential confounders. However, efflux capacity at baseline significantly predicted graft failure (HR, 0.43; 95% CI, 0.29 to 0.64; P<0.001) independent of apolipoprotein A-I, HDL cholesterol, or creatinine clearance. In conclusion, this prospective study shows that cholesterol efflux capacity from macrophage foam cells is not associated with cardiovascular or all-cause mortality but is a strong predictor of graft failure independent of plasma HDL cholesterol levels in renal transplant recipients.

| S-EPMC4731105 | biostudies-literature

Plasma secretory phospholipase A2-IIa as a potential biomarker for lung cancer in patients with solitary pulmonary nodules.

Project description:BackgroundFive-year survival for lung cancer has remained at 16% over last several decades largely due to the fact that over 50% of patients are diagnosed with locally-advanced or metastatic disease. Diagnosis at an earlier and potentially curable stage is crucial. Solitary pulmonary nodules (SPNs) are common, but the difficulty lies in the determination of which SPN is malignant. Currently, there is no convenient and reliable biomarker effective for early diagnosis. Secretory phospholipase A2-IIa (sPLA2-IIa) is secreted into the circulation by cancer cells and may allow for an early detection of lung cancer.MethodsPlasma samples from healthy donors, patients with only benign SPN, and patients with lung cancer were analyzed. Expression of sPLA2-IIa protein in lung cancer tissues was also determined.ResultsWe found that the levels of plasma sPLA2-IIa were significantly elevated in lung cancer patients. The receiver operating characteristic curve analysis, comparing lung cancer patients to patients with benign nodules, revealed an optimum cutoff value for plasma sPLA2-IIa of 2.4 ng/ml to predict an early stage cancer with 48% sensitivity and 86% specificity and up to 67% sensitivity for T2 stage lung cancer. Combined sPLA2-IIa, CEA, and Cyfra21.1 tests increased the sensitivity for lung cancer prediction. High level of plasma sPLA2-IIa was associated with a decreased overall cancer survival. sPLA2-IIa was overexpressed in almost all non-small cell lung cancer and in the majority of small cell lung cancer by immunohistochemistry analysis.ConclusionOur finding strongly suggests that plasma sPLA2-IIa is a potential lung biomarker to distinguish benign nodules from lung cancer and to aid lung cancer diagnosis in patients with SPNs.

| S-EPMC3250967 | biostudies-literature

Total direct chemical synthesis and biological activities of human group IIA secretory phospholipase A2.

Project description:Human group IIA secretory phospholipase A(2) (hGIIA sPLA(2)) is reported to be involved in inflammation, since its expression level is enhanced under various inflammatory conditions. In this work, we report the total chemical synthesis of this enzyme (124 amino acids) by solid-phase method. The identity of the protein, in denatured or folded (7 disulphide bonds) forms, was confirmed by electrospray MS. Synthetic sPLA(2) possesses the same circular dichroism spectrum, enzymic activity in hydrolysing different phospholipid substrates, and inhibitory effect in thrombin formation from prothrombinase complex as the recombinant sPLA(2). Furthermore, LY311727, a reported specific hGIIA sPLA(2) inhibitor, is able to inhibit the synthetic and the recombinant enzymes with the same efficiency. This study demonstrates that chemically continuous solid phase synthesis is an alternative and less time-consuming approach to producing small, structurally folded and fully active proteins of up to 124 amino acids, such as hGIIA sPLA(2). Moreover, this technique provides more flexibility in analogue synthesis to elucidate their physiological functions and pathological effects.

| S-EPMC1222685 | biostudies-other

Group IIA secretory phospholipase 2 independently predicts mortality and positive blood culture in emergency department sepsis patients.

Project description:ObjectiveThe IIA isoform of phospholipase A2 is an acute phase reactant that increases in sepsis, although data regarding its prognostic value are limited. We hypothesized that group IIA secretory phospholipase A2 (sPLA2-IIA) predicts sepsis mortality and positive cultures and sought to compare its predictive characteristics to lactate and procalcitonin.MethodssPLA2-IIA and procalcitonin levels were measured at enrollment in emergency department patients with early severe sepsis and compared with lactate levels. The primary outcome was in-hospital mortality. The secondary outcome was any positive culture with a sub-group analysis of only blood-culture positive patients. Optimum cut-point was determined using receiver operating characteristics curves. A multivariable model was developed to test the independent prognostic value of elevated sPLA2-IIA to predict mortality.ResultsOf the 192 patients in the cohort, 160, 153, and 158 had samples available for analysis of sPLA2-IIA, procalcitonin, and lactate, respectively. A total of 21% of patients met the primary outcome of in-hospital mortality. At a 100 ng/mL threshold for sPLA2-IIA, adjusted odds to predict mortality were 3.78 (95% confidence interval = 1.14-12.56, P = 0.03). sPLA2-IIA and procalcitonin were both elevated in culture-positive patients; however, the difference was not statistically significant. sPLA2-IIA was significantly higher in blood culture-positive patients.ConclusionAn elevated level of sPLA2-IIA was associated with increased mortality in sepsis patients. sPLA2-IIA levels, unlike procalcitonin, also were significantly higher in blood culture-positive patients.

| S-EPMC8212558 | biostudies-literature

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

Project description: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 compl pathological conditions including various cancers. Here ete 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.

| S-EPMC5599634 | biostudies-literature

Secretory phospholipase A2-IIa is involved in prostate cancer progression and may potentially serve as a biomarker for prostate cancer.

Project description:The majority of prostate cancers are indolent, whereas a significant portion of patients will require systemic treatment during the course of their disease. To date, only high Gleason scores are best associated with a poor prognosis in prostate cancer. No validated serum biomarker has been identified with prognostic power. Previous studies showed that secretory phospholipase A2-IIa (sPLA2-IIa) is overexpressed in almost all human prostate cancer specimens and its elevated levels are correlated with high tumor grade. Here, we found that sPLA2-IIa is overexpressed in androgen-independent prostate cancer LNCaP-AI cells relative to their androgen-dependent LNCaP cell counterparts. LNCaP-AI cells also secrete significantly higher levels of sPLA2-IIa. Blocking sPLA2-IIa function compromises androgen-independent cell growth. Inhibition of the ligand-induced signaling output of the HER network, by blocking PI3K-Akt signaling and the nuclear factor-kappaB (NF-κB)-mediated pathway, compromises both sPLA2-IIa protein expression and secretion, as a result of downregulation of sPLA2-IIa promoter activity. More importantly, we demonstrated elevated serum sPLA2-IIa levels in prostate cancer patients. High serum sPLA2-IIa levels are associated significantly with high Gleason score and advanced disease stage. Increased sPLA2-IIa expression was confirmed in prostate cancer cells, but not in normal epithelium and stroma by immunohistochemistry analysis. We showed that elevated signaling of the HER/HER2-PI3K-Akt-NF-κB pathway contributes to sPLA2-IIa overexpression and secretion by prostate cancer cells. Given that sPLA2-IIa overexpression is associated with prostate development and progression, serum sPLA2-IIa may serve as a prognostic biomarker for prostate cancer and a potential surrogate prostate biomarker indicative of tumor burden.

| S-EPMC2981059 | biostudies-literature

Simplified YM-26734 inhibitors of secreted phospholipase A2 group IIA.

Project description:Simplified analogs of YM-26734, a known inhibitor of secreted phospholipase A(2) (sPLA(2)) group IIA, were synthesized and found to also display potent inhibition at low nanomolar concentrations. Analogs were based on the didodecanoylphloroglucinol portion of YM-26734 which contains the predicted active site calcium binding group.

| S-EPMC2578825 | biostudies-literature

Phospholipase A2 Group IIA Is Associated with Inflammatory Hepatocellular Adenoma.

Project description:Although benign hepatocellular adenomas (HCA) are very rare, recent observations have shown their occurrence in patients with diabetes mellitus. Consequently, most of these cases are treated by resection due to concerns regarding their potential progression to hepatocarcinoma (HCC). This decision is largely driven by the limited number of studies on HCC subtyping and the lack of molecular and biological insights into the carcinogenic potential of benign tumors. This study aimed to comprehensively investigate the subtype classification of HCA and to compare and analyze gene expression profiling between HCA and HCC tissues. One fresh inflammatory HCA (I-HCA), three non-B non-C HCCs, two hepatitis B virus-HCCs, and one normal liver tissue sample were subjected to single-cell RNA sequencing (scRNA-seq). Comparative analysis of scRNA-seq among different tissues showed that phospholipase A2 group IIA (PLA2G2A) mRNA was specifically expressed in I-HCA, following RNA-seq analysis in formalin-fixed paraffin-embedded tissues from other HCAs. Immunohistochemistry using the PLA2G2A antibody in these tissues indicated that the positive reaction was mainly observed in hepatocytes of I-HCAs and stromal cells surrounding the tumor tissue in HCC were also stained. According to a clinical database, PLA2G2A expression in HCC does not correlate with poor prognosis. This finding may potentially help develop a new definition for I-HCA, resulting in a significant clinical contribution, but it requires validation with other fresh HCA samples.

| S-EPMC10778238 | biostudies-literature

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.

Project description: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.

| S-EPMC5495423 | biostudies-literature

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