Soluble glycoprotein 130 is inversely related to severity of coronary atherosclerosis.

PURPOSE: Recent studies indicate that the effects of interleukin 6 (IL-6) realized via soluble IL-6 receptor (sIL-6R) facilitate the development of various pathological processes. Soluble gp130 (sgp130) is a naturally occurring inhibitor of signal transduction via this pathway. In this study, we assessed the relationship between circulating levels of IL-6, sIL-6R and sgp130 and severity of coronary atherosclerosis in patients with stable coronary artery disease (CAD). METHODS: Plasma levels of IL-6, sIL-6R and sgp130 were measured in patients with atherosclerotic coronary lesions (n = 128, group 1) and with intact coronary arteries (n = 48, group 2). The severity of coronary atherosclerosis was evaluated by the number of affected arteries and by Gensini Score index. RESULTS: Circulating IL-6 levels in group 1 were significantly higher than those in group 2. The levels of sIL-6R did not differ considerably in both the groups. The levels of sgp130 in group 1 were significantly lower than in group 2. A negative correlation has been revealed between sgp130 levels and the number of affected coronary arteries and Gensini Score index. CONCLUSIONS: Serum concentration of sgp130 in patients with stable CAD is inversely related to severity of coronary damage. Low sgp130 level may serve as an additional indicator of coronary atherosclerosis severity.

The association of PLA2G2A single nucleotide polymorphisms with type IIa secretory phospholipase A2 level but not its activity in patients with stable coronary heart disease.

BACKGROUND: Single nucleotide polymorphisms (SNPs) of the secretory phospholipase A2 type IIa (sPLA-IIa) gene (PLA2G2A) affect sPLA2-IIa level and activity in patients with diabetes mellitus, acute coronary syndrome or recent cardiovascular surgical interventions. Our study examined the effects of PLA2G2A SNPs on sPLA2-IIa levels and activity in patients with stable CHD. METHODS AND RESULTS: The study included a total of 396 patients (30% women). Six SNPs of PLA2G2A: rs1774131, rs11573156, rs3753827, rs2236771, rs876018, and rs3767221, sPLA2-IIa level and activity were determined for all patients. Four SNPs (rs1774131, rs11573156, rs3753827, rs3767221) correlated with sPLA2-IIa level but not activity with the strongest correlation observed for rs11573156 (r=0.49, p=3.7·10(-13)). All partial correlations controlling for rs11573156 became insignificant, whereas, the partial correlation of rs11573156 with sPLA2-IIa level controlling for other SNPs remained significant. Only rs11573156 showed association with sPLA2-IIa level in multiple regression analysis. Haplotype CGGGTT was associated with a significantly higher sPLA2-IIa level but not activity compared with all other haplotypes after adjustment for gender, age, diabetes mellitus and statin use (p=0.0023). CONCLUSIONS: According to our results the examined SNPs affect the sPLA2-IIa level to a greater extent than its activity in patients with stable CHD. It seems that, the impact of these SNPs on sPLA2-IIa level is caused by their linkage to rs11573156 whose minor alleles were associated with higher sPLA2-IIa level. At the same time haplotype CGGGTT, which includes the minor allele of rs11573156, was the dominant haplotype and was associated with the highest sPLA2-IIa level.

Oxidized phosphatidylcholine stimulates activity of secretory phospholipase A2 group IIA and abolishes sphingomyelin-induced inhibition of the enzyme.

We have shown recently that oxidized but not native lipoproteins stimulate the activity of secretory phospholipase A2 group IIA (sPLA(2)(IIA)). Since oxidized lipoproteins potentially contain considerable amounts of oxidized phosphatidylcholine, we examined the effect of oxidized palmitoyl arachidonyl phosphatidylcholine (oxPC) and the competitive effects of oxPC and sphingomyelin (SM) on sPLA(2)(IIA) activity. OxPC either added to the assay medium as separated liposomes or incorporated in varied amounts into LDL progressively enhanced the activity of purified human sPLA(2)(IIA) and abolished the inhibitory effect of LDL-incorporated SM on the enzyme activity. OxPC completely abolished the inhibitory effect of SM at the oxPC/SM concentration ratio 1/2. On the other hand, SM suppressed the activating effect of oxPC in a dose-dependent manner, abolishing it almost completely at a concentration 8 times as high as that of oxPC. Thus, changes in the oxPC/SM concentration ratio in LDL may affect the regulatory mechanisms of sPLA(2)(IIA) activity in human blood, inducing stimulation or inhibition of the enzyme. Influence on regulation of sPLA(2)(IIA) activity can be useful in the development of new therapeutic approaches to the treatment of cardiovascular diseases.

Opposite effects of native and oxidized lipoproteins on the activity of secretory phospholipase A(2) group IIA.

Elevated circulating level and activity of secretory phospholipase A(2) group IIA (sPLA(2)(IIA)) are associated with the development of adverse cardiovascular events. The mechanisms of sPLA(2)(IIA) activity regulation in human blood serum so far remain obscure. We have suggested that the enzyme activity is influenced by circulating lipoproteins. The activity of sPLA(2)(IIA) was examined in whole serum of healthy individuals and after removal of lipoproteins from it. The effects of different classes of native and oxidized lipoproteins on sPLA(2)(IIA) in blood serum were compared with their effects on purified sPLA(2)(IIA). Activity of sPLA(2)(IIA) was not detected in whole serum despite the high concentration of the enzyme. However after lipoproteins had been removed from the serum, the lipoprotein-depleted serum displayed sPLA(2)(IIA) activity which was proportional to the amount of sPLA(2)(IIA) in it. Native LDL, HDL and VLDL+IDL inhibited the activity of both purified sPLA(2)(IIA) and the enzyme activity in lipoprotein-depleted serum. By contrast, oxidized LDL, HDL and VLDL+IDL significantly stimulated the activity of purified and serum sPLA(2)(IIA) and enhanced the release of fatty acids from the substrate. The data indicate that native and oxidized lipoproteins regulate catalytic activity of sPLA(2)(IIA). Activation of sPLA(2)(IIA) by oxidized lipoproteins may be regarded as one of the mechanisms of atherosclerosis development.

The catalytically active secretory phospholipase A2 type IIA is involved in restenosis development after PTCA in human coronary arteries and generation of atherogenic LDL.

Secretory phospholipase A2 type IIA (sPLA2) may actively contribute to atherogenesis, acting either within the arterial wall or in plasma. Proinflammatory eicosanoids and lysophospholipids, generated through hydrolysis of cell membrane phospho-lipids by sPLA2, initiate and prolong the inflammatory process. In the present study we examined the possible involvement of sPLA2 in development of restenosis in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). We also investigated whether serum sPLA2 could catalyze accumulation of lysophosphatidylcholine (LPC) in LDL. Concentrations and catalytic activities of sPLA2 were measured in blood serum of 49 consenting patients immediately before, 1-7 and 180 days after PTCA. All patients had repeat angiograms at 180-day follow-up. Restenosis was registered in 19 patients. Accumulation of LPC in LDL was evaluated by thin-layer chromatography after incubation of blood serum with LDL. Serum sPLA2 concentrations increased in all study patients by day 1 post-PTCA, but the increase was significantly greater and more protracted in patients who developed restenosis. Catalytic activities increased significantly 6 days post-PTCA in patients who developed restenosis, whereas for patients without restenosis there was no change in serum sPLA2 activity throughout the study period in spite of the sPLA2 presence in blood. Incubation of blood serum (6 days post-PTCA) with LDL resulted in accumulation of LPC only for those patients who subsequently developed restenosis. Manoalide, a specific inhibitor of sPLA2, completely blocked the LPC accumulation. The data indicate that elevated serum sPLA2 activity after PTCA is associated with restenosis development and may be involved in atherogenic modification of LDL in blood serum.