Dynein Separately Partners with NDE1 and Dynactin To Orchestrate T Cell Focused Secretion.

Helper and cytotoxic T cells accomplish focused secretion through the movement of vesicles toward the microtubule organizing center (MTOC) and translocation of the MTOC to the target contact site. In this study, using Jurkat cells and OT-I TCR transgenic primary murine CTLs, we show that the dynein-binding proteins nuclear distribution E homolog 1 (NDE1) and dynactin (as represented by p150(Glued)) form mutually exclusive complexes with dynein, exhibit nonoverlapping distributions in target-stimulated cells, and mediate different transport events. When Jurkat cells expressing a dominant negative form of NDE1 (NDE1-enhanced GFP fusion) were activated by Staphylococcus enterotoxin E-coated Raji cells, NDE1 and dynein failed to accumulate at the immunological synapse (IS) and MTOC translocation was inhibited. Knockdown of NDE1 in Jurkat cells or primary mouse CTLs also inhibited MTOC translocation and CTL-mediated killing. In contrast to NDE1, knockdown of p150(Glued), which depleted the alternative dynein/dynactin complex, resulted in impaired accumulation of CTLA4 and granzyme B-containing intracellular vesicles at the IS, whereas MTOC translocation was not affected. Depletion of p150(Glued) in CTLs also inhibited CTL-mediated lysis. We conclude that the NDE1/Lissencephaly 1 and dynactin complexes separately mediate two key components of T cell-focused secretion, namely translocation of the MTOC and lytic granules to the IS, respectively.

[Meta-analysis for the relationship between lipoprotein-associated phospholipase A2 and ischemic stroke].

OBJECTIVE: To analyze the relationship between lipoprotein-associated phospholipase A2 (Lp-PLA2) and ischemic stroke.
 Methods: Corresponding data, with case-control studies or cohorts regarding Lp-PLA2 and ischemic stroke, were retrieved from PubMed, Web of Science, Embase, the Cochrane Library, Chinese Biomedical Literature (CMB), VIP, China National Knowledge Infrastructure (CNKI), and Wanfang Database. Meta-analysis was performed by using Stata12.0.
 Results: Eight studies including 46 034 participants met the inclusion criteria. Meta-analysis showed that the combined effect of relative risk (RR) between Lp-PLA2 mass and ischemic stroke was [1.04 (0.98 to 1.11)] and that the combined effect of RR between Lp-PLA2 activity and ischemic stroke was [1.03 (0.96 to 1.10)], suggesting that Lp-PLA2 mass and activity were not associated with ischemic stroke.
 Conclusion: It cannot be considered that Lp-PLA2 mass and Lp-PLA2 activity was the risk factor for ischemic stroke.

Biosynthesis of oxidized lipid mediators via lipoprotein-associated phospholipase A2 hydrolysis of extracellular cardiolipin induces endothelial toxicity.

We (66) have previously described an NSAID-insensitive intramitochondrial biosynthetic pathway involving oxidation of the polyunsaturated mitochondrial phospholipid, cardiolipin (CL), followed by hydrolysis [by calcium-independent mitochondrial calcium-independent phospholipase A2-γ (iPLA2γ)] of oxidized CL (CLox), leading to the formation of lysoCL and oxygenated octadecadienoic metabolites. We now describe a model system utilizing oxidative lipidomics/mass spectrometry and bioassays on cultured bovine pulmonary artery endothelial cells (BPAECs) to assess the impact of CLox that we show, in vivo, can be released to the extracellular space and may be hydrolyzed by lipoprotein-associated PLA2 (Lp-PLA2). Chemically oxidized liposomes containing bovine heart CL produced multiple oxygenated species. Addition of Lp-PLA2 hydrolyzed CLox and produced (oxygenated) monolysoCL and dilysoCL and oxidized octadecadienoic metabolites including 9- and 13-hydroxyoctadecadienoic (HODE) acids. CLox caused BPAEC necrosis that was exacerbated by Lp-PLA2 Lower doses of nonlethal CLox increased permeability of BPAEC monolayers. This effect was exacerbated by Lp-PLA2 and partially mimicked by authentic monolysoCL or 9- or 13-HODE. Control mice plasma contained virtually no detectable CLox; in contrast, 4 h after Pseudomonas aeruginosa (P. aeruginosa) infection, 34 ± 8 mol% (n = 6; P < 0.02) of circulating CL was oxidized. In addition, molar percentage of monolysoCL increased twofold after P. aeruginosa in a subgroup analyzed for these changes. Collectively, these studies suggest an important role for 1) oxidation of CL in proinflammatory environments and 2) possible hydrolysis of CLox in extracellular spaces producing lysoCL and oxidized octadecadienoic acid metabolites that may lead to impairment of pulmonary endothelial barrier function and necrosis.

New risk factors for adult-onset incident asthma. A nested case-control study of host antioxidant defense.

RATIONALE: Host antioxidant defense, consisting of enzymatic antioxidant activity and nonenzymatic antioxidant micronutrients, is implicated in asthma pathogenesis. Studies of antioxidant defense and adult incident asthma have either used measures of antioxidants estimated from questionnaires or not considered enzymatic aspects of host defense. OBJECTIVES: We conducted the first study designed and powered to investigate the association of antioxidant defenses on adult incident asthma. METHODS: In a nested case-control study, we followed Shanghai women (aged 40-70 years) without prevalent asthma at baseline, over 8 years. Subjects with incident asthma were ascertained prospectively by gold standard testing of symptomatic women and matched to two asymptomatic control subjects. MEASUREMENTS AND MAIN RESULTS: Baseline urinary F2-isoprostanes, plasma concentrations of antioxidant micronutrients (tocopherols, xanthines, carotenes, and lycopene), and antioxidant enzyme activity (platelet-activating factor acetylhydrolase [PAF-AH] and superoxide dismutase) were measured from samples collected before disease onset. Among 65,372 women, 150 (0.24%) developed asthma. F2-isoprostane levels before asthma onset were not different between cases and control subjects. Doubling of α-tocopherol concentrations and PAF-AH activity was associated with 50 and 37% decreased risk of incident asthma (α-tocopherol: adjusted odds ratio = 0.52; 95% confidence interval, 0.32-0.84; PAF-AH: adjusted odds ratio = 0.63; 95% confidence interval, 0.42-0.93). CONCLUSIONS: In this prospective study, α-tocopherol, within normal reference ranges, and PAF-AH enzymatic activity were associated with decreased asthma development. These modifiable risk factors may be an effective strategy to test for primary asthma prevention.

[When we have learned about the brain development from a disease-oriented study: DBZ regulates cortical cell positioning and neurite extension by sustaining the anterograde transport of Lis1/DISC1 through control of Ndel1 phosphorylation].

Cell positioning and neuronal network formation are crucial for proper brain function. Disrupted-In-Schizophrenia 1 (DISC1) is anterogradely transported to the neurite tips, together with Lis1, and functions in neurite extension via suppression of GSK3ß activity. Then, transported Lis1 is retrogradely transported and functions in cell migration. Here, we show that DISC1-binding zinc finger protein (DBZ) regulates mouse cortical cell positioning and neurite development in vivo, together with DISC1. DBZ hindered Ndel1 phosphorylation at threonine 219 and serine 251. DBZ depletion or expression of a double-phosphorylated mimetic form of Ndel1 impaired the transport of Lis1 and DISC1 to the neurite tips and hampered microtubule elongation. Moreover, application of DISC1 or a GSK3ß inhibitor rescued the impairments caused by DBZ insufficiency or double-phosphorylated Ndel1 expression. We concluded that DBZ controls cell positioning and neurite development by interfering with Ndel1 from disproportionate phosphorylation, which is critical for appropriate anterograde transport of the DISC1-complex.

To hydrolyze or not to hydrolyze: the dilemma of platelet-activating factor acetylhydrolase.

Mounting ambiguity persists around the functional role of the plasma form of platelet-activating factor acetylhydrolase (PAF-AH). Because PAF-AH hydrolyzes PAF and related oxidized phospholipids, it is widely accepted as an anti-inflammatory enzyme. On the other hand, its actions can also generate lysophosphatidylcholine (lysoPC), a component of bioactive atherogenic oxidized LDL, thus allowing the enzyme to have proinflammatory capabilities. Presence of a canonical lysoPC receptor has been seriously questioned for a multitude of reasons. Animal models of inflammation show that elevating PAF-AH levels is beneficial and not deleterious and overexpression of PAF receptor (PAF-R) also augments inflammatory responses. Further, many Asian populations have a catalytically inert PAF-AH that appears to be a severity factor in a range of inflammatory disorders. Correlation found with elevated levels of PAF-AH and CVDs has led to the design of a specific PAF-AH inhibitor, darapladib. However, in a recently concluded phase III STABILITY clinical trial, use of darapladib did not yield promising results. Presence of structurally related multiple ligands for PAF-R with varied potency, existence of multi-molecular forms of PAF-AH, broad substrate specificity of the enzyme and continuous PAF production by the so called bi-cycle of PAF makes PAF more enigmatic. This review seeks to address the above concerns.

Lp-PLA2 is associated with structural valve degeneration of bioprostheses.

OBJECTIVES: In this study, we sought to determine the metabolic markers associated with structural valve degeneration (SVD). BACKGROUND: Structural valve degeneration (SVD) is the major cause of bioprosthetic valve failure leading to bioprostheses (BPs) stenosis or regurgitation. We hypothesized that lipoprotein-associated phospholipase A2 (Lp-PLA2) is involved in the SVD of BPs. METHODS: We included 197 patients who underwent aortic valve replacement with a bioprosthetic valve and had echocardiographic follow-up to evaluate valve function. Moreover, explanted BPs (n = 39) were analysed by immunohistochemistry for the expression of Lp-PLA2. RESULTS: After a mean follow-up of 7·9 ±0·2 years, forty-one patients (21%) were identified as developing SVD. Patients with SVD had significantly higher plasma level of Lp-PLA2 mass (151·8 ± 9·2 ng/mL vs. 133·2 ± 3·4 ng/mL, P = 0·03) and activity (27·6 ± 0·9 nmol/min/mL vs. 25·0 ± 0·4 nmol/min/mL, P = 0·005). Multivariate analysis revealed that Lp-PLA2 activity (OR: 1·09, 95% CI: 1·01-1·18; P = 0·03) was the strongest independent predictor of SVD. Immunohistochemistry studies of explanted BP showed that 77% of explanted BPs had the expression of Lp-PLA2, which correlated with the density of macrophages (CD68), and ox-LDL levels in bioprosthetic tissues. CONCLUSIONS: Increased blood plasma activity of Lp-PLA2 is associated with higher prevalence of SVD. These findings open new avenues for the identification of patients at risk for SVD and for the development of pharmacotherapy aiming at the prevention of SVD.

Three-dimensional regulation of radial glial functions by Lis1-Nde1 and dystrophin glycoprotein complexes.

Radial glial cells (RGCs) are distinctive neural stem cells with an extraordinary slender bipolar morphology and dual functions as precursors and migration scaffolds for cortical neurons. Here we show a novel mechanism by which the Lis1-Nde1 complex maintains RGC functions through stabilizing the dystrophin/dystroglycan glycoprotein complex (DGC). A direct interaction between Nde1 and utrophin/dystrophin allows for the assembly of a multi-protein complex that links the cytoskeleton to the extracellular matrix of RGCs to stabilize their lateral membrane, cell-cell adhesion, and radial morphology. Lis1-Nde1 mutations destabilized the DGC and resulted in deformed, disjointed RGCs and disrupted basal lamina. Besides impaired RGC self-renewal and neuronal migration arrests, Lis1-Nde1 deficiencies also led to neuronal over-migration. Additional to phenotypic resemblances of Lis1-Nde1 with DGC, strong synergistic interactions were found between Nde1 and dystroglycan in RGCs. As functional insufficiencies of LIS1, NDE1, and dystroglycan all cause lissencephaly syndromes, our data demonstrated that a three-dimensional regulation of RGC's cytoarchitecture by the Lis1-Nde1-DGC complex determines the number and spatial organization of cortical neurons as well as the size and shape of the cerebral cortex.

Platelet-activating factor acetylhydrolase and premature ovarian failure.

Premature ovarian failure (POF) appears to be a complex disease entity with several underlying etiopathogenic contributions including the possibility of multiple distinctly different autoimmune mechanisms, in which inflammatory autoimmunity targeted to ovarian-specific germline antigens (e.g., zona pellucida proteins or Mater) or differentiation/regulatory factors (e.g. inhibin-alpha) were regarded as one of the most crucial factors. Platelet-activating factor (PAF) and PAF class oxidized phospholipids stimulate the occurrence and development of inflammation and atherosclerosis. PAF acetylhydrolase (PAF-AH) can hydrolyze PAF and PAF class oxidized phospholipids and eventually prevent the body from the damage of these inflammatory mediators. These findings indicate a potential relationship between PAF-AH and POF thus have major implications for the future health of women who suffer with premature ovarian failure.

Phospholipase A2 enzymes and the risk of atherosclerosis.

Certain members of the phospholipase A(2) superfamily of enzymes have established causal involvement in atherosclerosis, thus at least two groups of this family of enzymes have been considered potential candidates for the prevention of cardiovascular events. Recently completed experimental animal studies, human biomarker data, vascular imaging studies, and genome-wide atherosclerosis studies provide the rationale for proceeding with clinical outcome trials directed at inhibition of secretory phospholipase A(2) and lipoprotein-associated phospholipase A(2). A clinical trial with the sPLA(2) inhibitor varespladib methyl was recently terminated, while clinical trials with the Lp-PLA(2) inhibitor darapladib are being conducted in coronary heart disease patients. This article reviews the available experimental animal and human trial evidence that serve as the basis for the development of these two classes of phospholipase A(2) inhibitors.

[Association of lipoprotein-associated phospholipase activity A2 with cardiovascular risk factors]. / Niveles de fosfolipasa A2 asociada a lipoproteína en sujetos sin enfermedad coronaria con riesgo cardiovascular variable.

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory biomarker involved in atherosclerosis and directly associated with cardiovascular events. AIM: To determine Lp-PLA2 levels in asymptomatic subjects with differing cardiovascular risk. MATERIAL AND METHODS: We studied 152 subjects aged 46 ± 11 years (69 women). We recorded traditional cardiovascular risk factors, creatinine, ultrasensitive C-reactive protein, fibrinogen, fasting lipids, blood sugar and activity levels of Lp-PLA2. Cardiovascular risk was classified according to the number of risk factors of each subject (0,1-2 or ≥ 3 risk factors). Besides, we calculated global Framingham risk score. RESULTS: The average Framingham score of participants was 6%. Twenty percent of participants had no risk factors, 46% had 1 or 2 and 34% had ≥ 3. Mean Lp-PLA2 levels were 185 ± 48 nmol/ml/min (201 ± 49 in men and 166 ± 38 in women). Lp-PLA2 correlated significantly (p < 0,05 for all) with non-HDL cholesterol, LDL, HDL, creatinine, waist circumference, body mass index and Framingham risk score. There was no correlation with blood sugar, C-reactive protein, fibrinogen or smoking status. Lp-PLA2 levels were significantly higher according to the number of risk factors: 0 factors: 163 ± 43, 1-2 factors: 185 ± 45 and ≥ 3 factors: 201 ± 47 nmol/ml/min, respectively. Linear regression analysis showed that the best predictor of Lp-PLA2 was non-HDL cholesterol (ß = 0,74; p < 0,0001). CONCLUSIONS: Lp-PLA2 activity increased along with the number of cardiovascular risk factors and was correlated mainly with non -HDL cholesterol.

Lipoprotein-associated phospholipase A2 (Lp-PLA2): a review of its role and significance as a cardiovascular biomarker.

OBJECTIVE: To conduct a comprehensive, systematic review of studies assessing the significance of lipoprotein-associated phospholipase A2 in cardiovascular diseases (CVDs). MATERIAL AND METHODS: A review of the literature was performed using the search term "Lipoprotein-associated phospholipase A2 (Lp-PLA2)" and each of the following terms: "cardiovascular risk," "cardiovascular death," "atherosclerotic disease," "coronary events," "transient ischemic attack (TIA)," "stroke," and "heart failure." The searches were performed on Medline, Google Scholar and ClinicalTrials.gov. RESULTS: The majority of published studies showed a significant association between Lp-PLA2 levels and cardiovascular events after multivariate adjustment. The association was consistent across a wide variety of subjects of both sexes and different ethnic backgrounds. CONCLUSIONS: The role of Lp-PLA2 as a significant biomarker of vascular inflammation was confirmed, and Lp-PLA2 seems to be closely correlated to cardiovascular events. It may be an important therapeutic target and may have an important role in prevention, risk stratification and personalised medicine.

Utility of Lp-PLA2 in lipid-lowering therapy.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a vascular-specific inflammatory marker. It is so named because of its association with low-density lipoprotein in plasma. Atherosclerosis is an inflammatory disease. Lp-PLA2 is recognized as a risk marker in primary or secondary prevention of atherosclerosis. Elevated Lp-PLA2 levels are associated with the increased risk for cardiovascular events, even after multivariable adjustment for traditional risk factors. Patients with dyslipidemia are shown to benefit largely from the modification of Lp-PLA2. The degree of coronary artery disease (0-, 1-, 2-, or 3-vessel disease) and plasma low-density lipoprotein cholesterol significantly correlated to Lp-PLA2 levels. The low biologic fluctuation and high vascular specificity of Lp-PLA2 make it possible to use a single measurement in clinical decision making, and it also permits clinicians to follow the Lp-PLA2 marker serially. Simvastatin significantly reduces macrophage content, lipid retention, and the intima to media ratio but increased the content of smooth muscle cells in atherosclerotic lesions. Statin treatment markedly reduced Lp-PLA2 in both plasma and atherosclerotic plaques with attenuation of the local inflammatory response and improved plaque stability due to reduced inflammation and decreased apoptosis of macrophages. Darapladib, an inhibitor of Lp-PLA2 when added to lipid-lowering therapy such as statins, offers great benefit in the reduction of plaque formation. This article explores the atherosclerotic process at molecular level, role of Lp-PLA2 in atherosclerosis, the effect of lipid-lowering drugs on Lp-PLA2, effect of direct Lp-PLA2 inhibitor darapladib in the atherosclerosis process, the therapeutic implications of Lp-PLA2 as risk marker, and finally the net effect on plaque stabilization.

Lp-PLA2- a novel risk factor for high-risk coronary and carotid artery disease.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is at the crossroads of lipid metabolism and the inflammatory response. It is produced by inflammatory cells, bound to LDL and other lipoproteins, and once in the arterial wall facilitates hydrolysis of phospholipids. Elevated serum levels of Lp-PLA2 have been associated with increased cardiovascular risk in healthy populations and in patients with known vascular disease. Here, we review the role of Lp-PLA2 in the development of atherosclerosis and progression to unstable disease, the utility of Lp-PLA2 as a risk predictor for coronary and carotid events and the potential clinical benefit of pharmacologic inhibition of Lp-PLA2.

PAF-acetylhydrolase expressed during megakaryocyte differentiation inactivates PAF-like lipids.

Platelet activating factor (PAF) and PAF-like lipids induce inflammatory responses in target cells. These lipid mediators are inactivated by PAF-acetylhydrolase (PAF-AH). The PAF signaling system affects the growth of hematopoietic CD34(+) cells, but roles for PAF-AH in this process are unknown. Here, we investigated PAF-AH function during megakaryopoiesis and found that human CD34(+) cells accumulate this enzymatic activity as they differentiate toward megakaryocytes, consistent with the expression of mRNA and protein for the plasma PAF-AH isoform. Inhibition of endogenous PAF-AH activity in differentiated megakaryocytes increased formation of lipid mediators that signaled the PAF receptor (PAFR) in fully differentiated human cells such as neutrophils, as well as megakaryocytes themselves. PAF-AH also controlled megakaryocyte alpha(IIb)beta(3)-dependent adhesion, cell spreading, and mobility that relied on signaling through the PAFR. Together these data suggest that megakaryocytes generate PAF-AH to modulate the accumulation of intracellular phospholipid mediators that may detrimentally affect megakaryocyte development and function.

Influence of propofol and volatile anaesthetics on the inflammatory response in the ventilated lung.

BACKGROUND: The immunomodulatory effects of volatile anaesthetics in vitro and the protective effect of propofol in lung injury spurred us to study the effects of volatile anaesthetics and propofol on lung tissue in vivo. METHODS: Twenty-seven pigs were randomized to 4-h general anaesthesia with propofol (8 mg/kg/h, group P, n=9), sevoflurane [minimum alveolar concentration (MAC)=1.0, group S, n=9) or desflurane (MAC=1.0, group D, n=9). Four healthy animals served as the no-ventilation group. Bronchoalveolar lavage fluid (BALF) was obtained to measure the cell counts, platelet-activating factor acetylhydrolase (PAF-AcH), phospholipase A(2) (PLA(2)) and superoxide dismutase (SOD) activity. Lung tissues were evaluated histologically and for caspase-3 expression. RESULTS: Volatile anaesthetics reduced PAF-AcH levels without affecting PLA(2) activity and resulted in decreased alveolar macrophage and increased lymphocyte counts in BALF (sevoflurane: 29 ± 23%; desflurane: 26 ± 6%, both P<0.05 compared with 4 ± 2% in the no-ventilation group). These findings were accompanied by atelectasis and inflammatory cells' infiltration in the inhalational anaesthetics groups. Also, sevoflurane reduced SOD activity and both sevoflurane and desflurane induced significant caspase-3 expression. In contrast, propofol resulted in a minor degree of inflammation and preserved BALF cells' composition without triggering apoptosis. CONCLUSION: Halogenated anaesthetics seem to trigger an immune lymphocytic response in the lung, inducing significant apoptosis and impairment of PAF-AcH. In contrast, propofol preserves anti-inflammatory and anti-oxidant defences during mechanical ventilation, thus preventing the emergence of apoptosis.

Anti-oxidant properties of high-density lipoprotein and atherosclerosis.

1. High-density lipoprotein (HDL) is one of the major carriers of cholesterol in the blood. It attracts particular attention because, in contrast with other lipoproteins, many physiological functions of HDL influence the cardiovascular system in favourable ways unless HDL is modified pathologically. 2. The best known function of HDL is the capacity to promote cellular cholesterol efflux from peripheral cells and deliver cholesterol to the liver for excretion, thereby playing a key role in reverse cholesterol transport. The functions of HDL that have recently attracted attention include anti-inflammatory and anti-oxidant activities. High anti-oxidant and anti-inflammatory activities of HDL are associated with protection from cardiovascular disease. 3. Atheroprotective activities, as well as a functional deficiency of HDL, ultimately depend on the protein and lipid composition of HDL. Conversely, these activities are compromised in many pathological states associated with inflammation. 4. The focus of the present review is on the anti-oxidant and anti-inflammatory functions of HDL and its individual components in relation to protection from atherosclerosis.

[Does Lp-PLA2 determination help predict atherosclerosis and cardiocerebrovascular disease?]. / Moze li odredivanje Lp-PLA2 pomoci u predvidanju ateroskleroze i kardiocerebrovaskularnih bolesti?

Thorough control of risk factors is pivotal for cardiocerebrovascular diseases. As classic risk assessment accounts for only 50% of risk variability and due to the role of inflammatory processes in endothelial dysfunction and atherosclerotic plaque rupture, it is necessary to identify new biomarkers for risk prediction. In addition to the inflammatory marker high sensibility C-reactive protein (hs-CRP), lipoprotein associated phospholipase A2 (Lp-PLA2) is gaining increasing significance, since it is directly involved in the pathogenesis of atherosclerotic plaque progression. Lp-PLA2 is highly specific for vascular inflammation, has low biological variability, and plays a causative role in atherosclerotic plaque inflammation. It belongs to the group of intracellular and secretory phospholipase enzymes that can hydrolyze sn-2 phospholipid ester bond of cellular membranes and lipoproteins. Lp-PLA2 enzyme is formed by macrophages and foam cells in atherosclerotic plaque, and is associated primarily with LDL particles in blood. Lp-PLA2 that is bound to LDL is the sole enzyme responsible for hydrolysis of oxidized phospholipids (oxPL) on LDL particles. Lp-PLA2 hydrolyzes oxPL at the surface of lipoproteins, but has weak activity against non-oxPL. Lp-PLA2 is also the enzyme that hydrolyzes oxPL on HDL particles, where it may have a role in the antioxidative function of HDL. The distribution of Lp-PLA2 between LDL and HDL particles depends on the extent of Lp-PLA2 glycosylation, which may affect the activity of Lp-PLA2 in plasma. Stable atherosclerotic plaques contain few inflammatory cells and a small amount of Lp-PLA2. In contrast, unstable plaques most often do not have significant impact on arterial lumen but may be detected by its thin connective tissue cap, low collagen and high lipid content. A distinguishing factor between stable and unstable atherosclerotic plaque may also be the presence of activated inflammatory cells and increased Lp-PLA2 concentration in unstable plaque. These new insights indicate that Lp-PLA2 may be a risk factor, which is important for the formation of atherosclerotic plaque but also for its rupture. The purpose of applying markers of inflammation is to improve stratification of patients at risk, so that treatment intensity may be adjusted to the risk level. Lp-PLA2 inhibition is associated with decreased cytokines. Lipid-affecting drugs stabilize atherosclerotic plaque by reducing the central lipid core, decreasing macrophage infiltration, and thickening of the connective tissue cap. These drugs reduce Lp-PLA2 concentration and the frequency of cardiocerebrovascular events as well. Besides acting as a specific marker of atherosclerotic plaque inflammation, Lp-PLA2 has a significant prognostic value because of its direct role in the formation of rupture-prone atherosclerotic plaque, unlike classic risk factors, for example lipid measurement or vascular imaging, which do not directly estimate acute ischemic potential in the arterial wall. Studies have demonstrated correlation between increased Lp-PLA2 concentrations and enhanced risk of cardiocerebrovascular events, even after multivariate adjustment to classic risk factors. In addition to its high specificity for vascular inflammation, Lp-PLA2 concentration is stable in terms of time, unlike, for instance, CRP levels. Lp-PLA2 has been confirmed as an independent risk predictor, which is complementary to hsCRP. It could be used in clinical practice for improved risk assessment in patients with transient cardiocerebrovascular risk, particularly in those with metabolic syndrome (obese patients with mixed dyslipidemia, hyperglycemia, insulin resistance, and arterial hypertension). Lp-PLA2 levels allow for further risk stratification of high-risk patients into a very high risk group where more aggressive therapy is recommended, as well as the achievement of LDL-cholesterol levels < 2.5 or, even better, < 2.0 mmol/L as a feasible therapeutic target. Similar to hsCRP, the levels of Lp-PLA2 are reduced by lipid-affecting drugs, while its low concentrations are associated with a very low risk of cardiocerebrovascular events both in low- and high-risk population. According to recent American guidelines for assessing the risk of cardiovascular disease, Lp-PLA2 determination is recommended as an additional marker to the classic risk assessment in patients with moderate and high risk.