LpPLA2
Biological or Clinical Significance of LpPLA2 Mass (Lipoprotein-associated Phospholipase A2)
- Gene encoding the Lp-PLA2 protein (PLA2G7)
- 12 exons
- On chromosome 6p21.2-12 [24]
- calcium-independent serine lipase [18]
- Associated with
- Low-density lipoprotein (LDL) in human plasma and serum
- Distinct from other phospholipases, such as
- Various secretory and cytosolic types of PLA2 [18]
- Produced by macrophages
- Expressed in greater concentrations in atherosclerotic lesions
- Lp-PLA2 participates in the oxidative modification of LDL
- By hydrolyzing oxidized phosphatidylcholines generating
- Lysophosphatidylcholine
- Oxidized free fatty acids [18]
- Both of which are potent proinflammatory products
- V.s. contribute to the formation of atherosclerotic plaques [18]
- Plasma Lp-PLA2 is independently associated with the risk for development of coronary heart disease
- Firmly implicated in release of lysophospholipid and oxidized fatty acids in lipoprotein(a) (Lp(a)) particles
- May help to explain the increased risk for CHD in subjects with elevated levels of serum Lp(a) [18]
- Generating pro-inflammatory and pro-atherogenic compounds from oxidized LDL in the vessel wall
- Increased levels of Lp-PLA2 mass or activity are associated with
- Increased risk for cardiovascular outcomes
- Might improve risk stratification
- Endothelial dysfunction [19]
- Early atherosclerosis [19]
- Products of Lp-PLA2 activity are generated mainly in the vascular wall [20]
- Secretory phospholipase A2 group VII (sPLA2-VII)
- Platelet activating factor acetylhydrolase (PAF-AH)
- Widely expressed in cells involved in atherosclerosis
- Macrophages,
- T-cells,
- Lymphocytes
- Mast cells [19]
- Jaterních buňkách [23]
- calcium-independent serin lipase
- Hydrolyzes phospholipids at the sn-2 position
- Preferentially on water-soluble polar phospholipids
- Particularly those with oxidatively truncated fatty acids [19]
- Specific protein-protein interaction between
- N-terminus of Lp-PLA2
- C-terminus of apolipoprotein B (apoB)
- = two-third of the Lp-PLA2 circulates primarily bound to LDL cholesterol
- = remaining third is distributed between
- High-density lipoprotein (HDL) cholesterol
- Very-low-density lipoproteins (VLDL) [19]
- Oxidation of LDL cholesterol within the arterial wall
- Substrate for the hydrolytic action of Lp-PLA2
- A short acyl group at the sn-2 position of phospholipids
- By cleaving an oxidized phosphatidylcholine component of the lipoprotein particle, Lp-PLA2 generates
- Potent proinflammatory and proatherogenic mediators like
- Ox-FA´s
- Promote atherosclerosis by directly
- Indirectly increasing oxidative stress
- Presence of oxidized LDL and other lipoproteins in the plasma and arterial walls
- Initiating fatty streak formation
- Arachidonic acid
- Cyclooxygenase converts it to inflammatory mediators
- Thromboxanes
- Leukotrienes [19]
- Lyso-PCs
- Pro-atherogenic in various early steps of atherosclerosis
- Expressed by macrophages in human atherosclerotic lesions
- Increased 5-fold in oxidized LDL compared to normal LDL [19]
- In the arterial wall upregulate adhesive molecules like
- Vascular cell adhesion molecule (VCAM)-1
- Intercellular adhesion molecule (ICAM)-1 [19]
- Promote monocyte migration
- Inducing monocyte chemotactic protein (MCP)-1
- In a concentration-dependent manner stimulate in macrophages
- IL -1beta
- IL-6
- Tumor necrosis factor (TNF)-alpha
- Scavenger receptor expression [19]
- Upregulate Lp-PLA2 activity
- Viscous cycle
- Pro-inflammatory mediators are becoming increasingly upregulated
- Plaque progression and destabilization [19]
- Lp-PLA2 is a suitable marker to predict CVD
- More specific cardiac marker to predict CVD when compare to conventional markers
- Independent advanced predictor of CVD
- Needs to be further evaluated by follow-up studies with better sample size in South Indian population [22]
- Lp-PLA2 se nezvyšuje za podmínek systémového zánětu
- Je proto specifickým markérem pro zánět cév
- Relativně malá biologická variabilita, její specificita a nezávislost na ostatních rizikových faktorech
- Významný marker pro detekci a monitorování kardiovaskulárního rizika [23]
- LpPLA2
- V nestabilních ateromatózních plátech
- S tenkou fibrózní čapkou
- Velkým tukovým jádrem, které jsou náchylné k ruptuře [23]
- Koncentrace LpPLA2 má více vztah ke kvalitě plátu než k jeho velikosti [23]
- Catalyze the hydrolysis of platelet-activating factor (PAF)
- Lp-PLA2 was originally referred to as PAF-acetylhydrolase before adopting its current name [24]
- Thereby indirect inhibition of platelet activation [24]
- Specificity for a wide variety of polar phospholipids
- Including oxidized and short-chain phospholipids [24]
- Vidím její roli jako snahu našeho organismu reagovat na oxidované fosfolipidy
- Rozložit je a přilákat makrofágy, aby zajistili odklizení
- Problém však je, pokud těch oxidovaných fosfolipidů se nám v těle tvoří hodně
- A to může například dělat třeba Chlamydia pneumonia v endotelu, nebo kouření cigaret, zvýšená střevní propustnost, deficit Selenu, rtuť, homocystein,...aj.
- Samotné zablokování Lp-PLA2 tedy nevyřeší příčinu obtíží, jen bude modulovat průběh - zmírní rychlost progrese...nestabilitu plátů
- Dokud je však její hladina zvýšená, je jasné, že máme problém...
- In humans, Lp-PLA2 expression is upregulated in
- Unstable and ruptured carotid artery plaques
- Along with increased concentrations of lysoPC [24]
Specific inhibitor of the enzyme
- Hyperlipidemic diabetic pig model
- Increased Lp-PLA2 in the vessel wall is associated
- More vulnerable plaque phenotype
- Can be modulated by inhibiting Lp-PLA2 activity
- Progression of the necrotic core of the plaque can be retarded
- Inhibition of the pro-atherogenic and pro-inflammatory effects of Lp-PLA2
- May therefore contribute to decrease the residual risk in high risk patients already on polypharmacotherapy [19]
Darapladib
- Selective inhibitor of Lp-PLA2
- Small molecule developed in 2003 by GlaxoSmithKline (GSK) [19]
- Beneficial effects in a diabetic/hypercholesterolemic pig model
- 10 mg/kg darapladib per day [19:: 24 weeks
- Lp-PLA2 activity in plasma was reduced by 89% in the treatment group (p < 0.00001 vs. placebo)
- Coronary gene expression
- Reduction of the expression of 24 genes associated with macrophage and T-cell function
- Selective Lp-PLA2 inhibition may promote lesion stabilization
- Median plaque area in the left anterior descending coronary artery was significantly reduced from 0.222 mm2 to 0.086 mm2 (p < 0.05)
- 7 of 17 control pigs showed a fibrous or thin fibrous cap atheroma
- Compared to 2 two out of 20 in the darapladib group (41% vs. 10%; p = 0.05)
- Necrotic area from the arterial section with the greatest plaque area was significantly reduced in the treatment group (0.87 ± 0.33 mm2 vs. 0.03 ± 0.003 mm2; p = 0.015 vs. placebo)
- Has demonstrated efficacy in three multicenter, randomized, double-blind, placebo-controlled trials [19]
- 14 days before elective carotid endarterectomy in 59 patients resulted in
- A significant systemic inhibition of Lp-PLA2 plasma activity by 80%
- Significantly reduced local Lp-PLA2 activity in atherosclerotic plaque
- Attenuated compared to placebo
- IL-18 levels
- Activity of the pro-apoptotic caspase-3 and caspase-8 [19]
- Darapladib (40, 80 and 160 mg, respectively) in 959 CHD and CHD-risk equivalent patients receiving aggressive lipid-lowering therapy
- Atorvastatin 20 or 80 mg per day (NCT00269048)
- 12 weeks of therapy, darapladib inhibited
- Lp-PLA2 activity in a dose-dependent manner
- Cca 43%, 55%, and 66% compared with placebo (p < 0.001 vs. placebo) [19]
- IL-6 and CRP displayed a strong decrease in the high-dose treatment group (12.6% and 13.0% decrease
- Levels of total cholesterol, LDL- and HDL cholesterol were not modified
- No major safety concerns were noted after 12 weeks of treatment [19]
- International, multicenter, randomized, double-blind, placebo-controlled IBIS-2
- 12 months of treatment with darapladib 160 mg daily in 330 patients with angiographically documented CHD
- Significantly reduced Lp-PLA2 activity levels (59% inhibition, p < 0.001 vs. placebo)
- Atheroma deformability measured by palpography (p = 0.22 vs. placebo)
- Plasma CRP lowering (p = 0.35 vs. placebo) were not met
- Placebo-treated group the necrotic core volume increased significantly (4.5 ± 17.9 mm3; p = 0.009)
- Darapladib halted this increase (-0.5 ± 13.9 mm3; 0.71) in the intervention group
- Higher systolic casual blood pressure in the darapladib group (3.0 mmHg, 95%CI 0.3-5.7; p = 0.031) [19]
- STABILITY trial (NCT00799903), a phase III, randomized, double-blind, placebo-controlled, parallel-assigned, multicenter clinical trial
- In 15,500 patients with chronic CHD [19]
- Orally active and reversible direct inhibitor of Lp-PLA2 enzyme activity
- In phase III testing
- Pre-clinical studies in diabetic and hypercholesterolemic pigs, darapladib reduced the necrotic core area and medial destruction
- Resulting in fewer lesions with an unstable phenotype [24]
- Inhibited Lp-PLA2 activity both in plasma and directly within atherosclerotic plaques
- Including a corresponding reduction in intra-plaque lysoPC
- Led to a downregulation of inflammatory gene expression, including
- 24 genes associated with T-lymphocyte and macrophage functioning
- Monocyte chemoattractant protein-1 (MCP-1)
- Chemokine receptor CCR2
- Marker of a subset of pro-inflammatory macrophages (M1 subtype) that is known to accumulate in atherosclerotic lesions [24]
- Plaque macrophage content was reduced with darapladib
- Did not modify plasma lipid levels [24]
IL-1 inhibition
- Causes a secondary decrease in HDL-LpPLA2 activity
- V.s. via reduction an excessively high nitrooxidative stress [21]
Loss-of-function (LOF) mutation (V279F allele) in the Lp-PLA2-encoding gene (PLA2G7)
- In individuals of Japanese, Chinese, and Korean descent
- Natural deficiency or absence of Lp-PLA2 activity
- Homozygotes completely lack Lp-PLA2 activity
- Heterozygotes have approximately a 50% reduction in Lp-PLA2 activity
- Two large case–control populations in Korean men
- Genetic deficiency in Lp-PLA2 activity due to carriage of the V279F null allele
- Associated with reduced odds of coronary heart disease by 31% [24]
- Single copy of the V279F allele
- Associated with a 21% reduction in the odds of CAD [24]
Odběr vzorku
- Analyte: Lipoprotein-Associated A2 Mass
- Specimen Type: Serum, EDTA Plasma
- Optimum Volume: 0.3 mL
- Stability:
- 2-8°C 1 week
- -20°C 1 month
- -70°C 4.7y; 9mo* [18]
- Reporting units: ng/mL
- Method: ELISA [18]
Zvýšení aktivity
Human abdominal subcutaneous adipocytes
- Active source of LpPLA2
- Influenced by fat depot and metabolic state [22]
Dalcetrapib
- Cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib
- No longer in development
- In phase II testing to increase Lp-PLA2 mass by approximately 17% as compared with placebo [24]
