Lipoprotein-Associated Phospholipase A2: A Novel Contributor in Sjögren's Syndrome-Related Lymphoma?

Background: B-cell non-Hodgkin's lymphoma (B-NHL) is one of the major complications of primary Sjögren's syndrome (SS). Chronic inflammation and macrophages in SS minor salivary glands have been previously suggested as significant predictors for lymphoma development among SS patients. Lipoprotein-associated phospholipase A2 (Lp-PLA2)-a product mainly of tissue macrophages-is found in the circulation associated with lipoproteins and has been previously involved in cardiovascular, autoimmune, and malignant diseases, including lymphoma. Objective: The purpose of the current study was to investigate the contributory role of Lp-PLA2 in B-NHL development in the setting of primary SS. Methods: Lp-PLA2 activity in serum samples collected from 50 primary SS patients with no lymphoma (SS-nL), 9 primary SS patients with lymphoma (SS-L), and 42 healthy controls (HC) was determined by detection of [3H]PAF degradation products by liquid scintillation counter. Moreover, additional sera from 50 SS-nL, 28 SS-L, and 32 HC were tested for Lp-PLA2 activity using a commercially available ELISA kit. Lp-PLA2 mRNA, and protein expression in minor salivary gland (MSG) tissue samples derived from SS-nL, SS-L patients, and sicca controls (SC) were analyzed by real-time PCR, Western blot, and immunohistochemistry. Results: Serum Lp-PLA2 activity was significantly increased in SS-L compared to both SS-nL and HC by two independent methods implemented [mean ± SD (nmol/min/ml): 62.0 ± 13.4 vs 47.6 ± 14.4 vs 50.7 ± 16.6, p-values: 0.003 and 0.04, respectively, and 19.4 ± 4.5 vs 15.2 ± 3.3 vs 14.5 ± 3.0, p-values: <0.0001, in both comparisons]. ROC analysis revealed that the serum Lp-PLA2 activity measured either by radioimmunoassay or ELISA has the potential to distinguish between SS-L and SS-nL patients (area under the curve [AUC]: 0.8022, CI [95%]: 0.64-0.96, p-value: 0.004 for radioimmunoassay, and AUC: 0.7696, CI [95%]: 0.66-0.88, p-value: <0.0001, for ELISA). Lp-PLA2 expression in MSG tissues was also increased in SS-L compared to SS-nL and SC at both mRNA and protein level. ROC analysis revealed that both MSG mRNA and protein Lp-PLA2 have the potential to distinguish between SS-nL and SS-L patients (area under the curve [AUC] values of 0.8490, CI [95%]: 0.71-0.99, p-value: 0.0019 and 0.9444, CI [95%]: 0.79-1.00, p- value: 0.0389 respectively). No significant difference in either serum Lp-PLA2 activity or MSG tissue expression was observed between SS-nL and HC. Conclusions: Lp-PLA2 serum activity and MSG tissue mRNA/protein expression could be a new biomarker and possibly a novel therapeutic target for B-cell lymphoproliferation in the setting of SS.

Effect of aliskiren on circulating endothelial progenitor cells and vascular function in patients with type 2 diabetes and essential hypertension.

BACKGROUND: The aim of this study was to investigate the effects of aliskiren on vascular function and endothelial progenitor cells (EPCs) in patients with type 2 diabetes and essential hypertension. METHODS: The study enrolled type 2 diabetic patients aged >50 years under stable glycemic control and first diagnosed mild essential hypertension. In phase A (n = 20), patients received aliskiren 150-300 mg daily for 3 months. In phase B (n = 12), hydrochlorothiazide (HCTZ) 12.5-25mg daily substituted for aliskiren for 3 more months. At baseline and at the end of each phase, we assessed (i) brachial blood pressure (BBP); (ii) central aortic systolic pressure (CSP), aortic augmentation index (Aix), and pulse wave velocity (PWV) as markers of arterial stiffness; (iii) brachial artery flow-mediated dilatation (FMD) as a marker of endothelial function; (iv) left ventricular (LV) twisting and untwisting as markers of LV function and (v) EPC numbers in culture of peripheral blood mononuclear cells. RESULTS: Aliskiren similarly reduced BBP and CSP, increased FMD (P < 0.001) and EPC numbers (P < 0.001), decreased PWV and Aix (P < 0.05), and improved LV twisting and untwisting (P < 0.05). Although substitution of HCTZ sustained BBP at similar levels, CSP and echocardiographic indices nearly returned at baseline levels, and the improvement of FMD, PWV, Aix, and EPC numbers was abolished. CONCLUSIONS: Aliskiren had a favorable effect on endothelial function and EPCs, reduced arterial stiffness, and improved LV twisting and untwisting. These effects were independent of BBP lowering, as they were not observed after the achievement of similar values of BBP with HCTZ.

Implication of lipoprotein associated phospholipase A2 activity in oxLDL uptake by macrophages.

Recognition and uptake of oxidized LDL (oxLDL) by scavenger receptors of macrophages and foam cell formation are mediated by the oxidatively modified apolipoprotein B (ApoB) and lipid moiety of oxLDL. A great amount of oxidized phosphatidylcholine (oxPC) of oxLDL is hydrolyzed at the sn-2 position by lipoprotein associated phospholipase A(2) (Lp-PLA(2)) to lysophosphatidylcholine and small oxidation products. This study examines the involvement of Lp-PLA(2) in the uptake of oxLDL by mouse peritoneal macrophages. LDL with intact Lp-PLA(2) activity [LDL(+)] and LDL with completely inhibited Lp-PLA(2) activity [LDL(-)] were subjected to oxidation with 5 microM CuSO(4) for 6 h [moderately oxLDL (MoxLDL)], or 24 h [heavily oxLDL (HoxLDL)] and peritoneal macrophages were incubated with these preparations. The uptake of MoxLDL(-) was about 30% increased compared with that of MoxLDL(+), and HoxLDL(-) uptake was about 20% increased compared with that of HoxLDL(+). Inhibition of Lp-PLA(2) activity had no effect on the uptake of ApoB-liposomes conjugates with ApoB isolated from MoxLDL(-), MoxLDL(+), HoxLDL(-), and HoxLDL(+). Liposomes prepared from the lipid extract of MoxLDL(-), MoxLDL(+), HoxLDL(-), and HoxLDL(+) exhibited a similar pattern to that observed in the uptake of the corresponding intact lipoproteins. This study suggests that the progressive inactivation of Lp-PLA(2) during LDL oxidation leads to an increased uptake of oxLDL by macrophages, which could be primarily attributed to the increased uptake of the oxidized phospholipids enriched lipid moiety of oxLDL.