Utility of Lp-pla2 in Lipid Lowering Therapy Essay

ABSTRACT
Lipoprotein- associated phopholipase A2 (Lp-PLA2) is a vascular-specific inflammatory marker. It is so named because of its association with low-density lipoprotein (LDL) 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 CAD (0-, 1-, 2- or 3-vessel disease) and plasma LDL cholesterol significantly correlated to Lp-PLA2 levels. Utility of Lp-pla2 in Lipid Lowering Therapy Essay. The low biologic fluctuation and high vascular specificity of Lp-PLA2 makes 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/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. Utility of Lp-pla2 in Lipid Lowering Therapy Essay.

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Utility of Lp-PLA2 in lipid lowering therapy
Introduction: Atherosclerosis is an inflammatory disease. Lp-PLA2 is recognized as a risk marker in primary or secondary prevention of atherosclerosis. Lp-PLA2 is so named because of its association with LDL in plasma1. Lp-PLA2 is also known as low density associated platelet-activating factor acetyl-hydrolase (PAF-AH) 2. Patients with dyslipidemia are shown to benefit largely from the modification of Lp-PLA23. Understanding the mechanism of atherosclerotic process is essential in knowing the utility of Lp-PLA2 in lipid lowering therapy. Inflammatory markers of atherosclerosis: Lp-PLA2 is a vascular-specific inflammatory marker4. Others include C-reactive protein (CRP), myeloperoxidase, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). Serum Lp-PLA2 level has higher sensitivity in predicting the vulnerability of the coronary atherosclerotic plaque than CRP5. Phospholipase inhibitors in atherosclerosis: The secreted PLA2 and Lp-PLA2 have been associated with atherogenesis and its complications. These two enzymes produce biologically active metabolites that are involved in several phases of the atherosclerosis process6.

Structure of LDL:
Low density lipoprotein (LDL) particles are the major cholesterol carriers in circulation and their physiological function is to carry cholesterol to the cells. In the process of atherogenesis these particles are modified and they accumulate in the arterial wall. LDL is a three-layer particle with outer surface, interfacial layer, and core. This structural information is utilized to understand and explain the molecular characteristics and interactions of modified, atherogenic LDL particles7. Phospholipids such as phophatidylcholine are located on the outersurface of LDL8. Phospholipid transfer protein (PLTP) was found to mediate transfer of anionic phospholipids to HDL and LDL, thereby neutralizing the effect of procoagulant liposomes resulting in a reduction of procoagulant activity9. Action of Lp-PLA2: It is an enzyme that catalyzes the hydrolysis of oxidized phopholipids on LDL to lyso-phospholipid and oxidized fatty acids in the atherosclerotic plaque (See figure 1). Inflammatory and Immunologic process in Atherosclerosis: It appears that Lp-PLA2 is released from the macrophages of atherosclerotic plaques into the circulation. A recent study showed a significant correlation between PLA2G7 RNA expression in plaque macrophages and plasma PAF-AH activity, which suggests that the latter is a consequence, rather than a cause of macrophage accumulation. It was also noticed that oxidized LDL can induce PAFAH, resulting in accumulation of lysophosphatidylcholine that increases the inflammatory action of oxidized LDL10, 11. Endothelial dysfunction is the earliest step in the atherosclerosis.Utility of Lp-pla2 in Lipid Lowering Therapy Essay.  Endothelial senenscence is brought about by various stress factors which include endothelial injury, NO depletion, and free radicals etc12. Molecules, such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and P-selectin, support the adhesion of monocytes and lymphocytes to the endothelium. LDL undergoes oxidation by the oxygen free radical released from the macrophages. Oxidation of LDL at the sites of endothelial damage is thought to be a major stimulus for uptake by macrophages, as oxidized LDL is considered to be autoantigen13. Lectin-like oxidized LDL receptor (LOX)-1 and scavenger receptor for phosphatidylserine and oxidized lipoprotein (SR-PSOX) are type II and I membrane glycoproteins, respectively, both of which can act as cell-surface endocytosis receptors for atherogenic oxidized LDL 14. Phagocytosis into macrophages through these scavenger receptors, causes the production of cytokines like Tumoral Necrosis Factor (TNF)- alpha, Interleukin (IL)-1 beta, IL-6, IL-12 and IL-18, among others. This secretion generates T cells activation into T helper lymphocytes (Th1), able to recognize the oxidised LDL and heat shock protein as autoantigens, amplifying the inflammatory response15. Lp-PLA2 hydrolyzes oxidized phospholipids in LDL to produce biologically active lysophosphatidylcholine and oxidized nonesterified fatty acids which contribute to atherosclerotic plaque instability and subsequent sudden coronary death16. Lysophosphotidyl choline activates several second messengers — including protein kinase C, extracellular-signal-regulated kinases, protein tyrosine kinases, and Ca(2+) — with a range of potentially atherogenic effects, including chemoattraction of monocytes, increased expression of adhesion molecules, and inhibition of endothelial nitric oxide production17. A critical event in the early stages of atherosclerosis is the focal accumulation of lipid-laden foam cells derived from macrophages. These foam cells tend to accumulate in the intimal layer of vascular wall. Death of macrophages and smooth muscle cells (SMC) can lead to progression of atherosclerosis18. The hydrolysis products of oxidised phospholipids may account for these cytotoxic and apoptosis-inducing effects on macrophages19. Defects in failure to resolve inflammation (which normally involves the suppression of inflammatory cell influx, effective clearance of apoptotic cells and promotion of inflammatory cell egress) promote the progression of atherosclerotic lesions into dangerous plaques20 (See figure 2). Lipid Lowering action of Statin: Cholesterol is known to participate in atheromatous plaque formation coming from blood stream and affecting vascular endothelium in environment of elevated LDL21. HMG-CoA reductase inhibitors (statins) are believed to inhibit cholesterol synthesis by inhibiting the following pathway and contribute to decreased LDL (See figure 3). Decreased cholesterol in the liver causes an upregulation of LDL receptors on the hepatocyte cell membrane, consequently, leading to the reduction in blood LDL levels. Statins decrease of LDL cholesterol and increase of HDL cholesterol slows down the evolution of atherosclerosis, stabilizes the atherosclerotic plaques, and even brings about their partial regression22. Utility of Lp-pla2 in Lipid Lowering Therapy Essay. Pleiotropic action of statin on plaque: Statin significantly reduces macrophage content, lipid retention and the intima/media ratio but increased the content of smooth muscle cells in atherosclerotic lesions. As Lp-PLA2 is considered to be releasing from the macrophages, reduction of macrophage has a significant effect in the formation of Lp-PLA223. Certain statins bind adhesion molecules, including functional leukocytic antigen-1, and therefore block their interaction with T lymphocytes and macrophages expressing the counter-receptor intercellular adhesion molecule-1 (ICAM-1)24. HMG-CoA reductase inhibitor, retards the initiation of atherosclerosis process through the improvement of NO bioavailability by both up-regulation of endothelial nitric oxide synthase mRNA and decrease of O(2)(-) production in vascular endothelial cells25. Bone marrow derived endothelial progenitor cells (EPCs) are early precursors of mature endothelial cells which replenish aging and damaged endothelial cells. DM results in significant impairment of bone marrow and circulating EPCs as well as endothelial function. The effect is ameliorated, in part, by atorvastatin independent of its cholesterol lowering effect. These data suggest a model wherein accelerated atherosclerosis seen with DM may, in part, result from reduction in EPCs which may be ameliorated by treatment with a statin26, 27. Oxidized low-density lipoprotein (oxLDL) is immunogenic. A recent study had determined the autoantibody titers against various forms of oxLDL in patients with acute coronary syndromes without persistent elevation of the ST segment (NSTE-ACS) and suggested an important role of the LDL-associated Lp-PLA(2) in modulating these immune responses. Moreover, the effect of early atorvastatin administration on these autoantibody titers was evaluated. From the 133 consecutive NSTE-ACS patients, 55 were eligible for the study. Thirty-four received atorvastatin (group A), whereas 21 did not received any hypolipidemic therapy (group B). Two forms of copper-oxidized LDL were prepared at the end of propagation or decomposition phase (oxLDL(P) or oxLDL(D), respectively). Similar types of oxLDL were prepared after previous inactivation of the endogenous Lp-PLA(2) [oxLDL(-)]. In group B, autoantibody titers of IgG class against oxLDL(P) and oxLDL(D) were elevated at 1 month of follow-up to reach the baseline values 3 months afterwards. By contrast the titers against oxLDL(-)(P) and oxLDL(-)(D) increased at 1 month of follow-up and remained elevated for up to 6 months of follow-up. Atorvastatin treatment prevented the elevation of autoantibody titers against all forms of oxidized LDL. We conclude that a short-term immune response against oxLDL(P) and oxLDL(D) (enriched in lyso-PC) and a chronic immune response against oxLDL(-)(P) and oxLDL(-)(D) (enriched in oxPL) are observed after an NSTE-ACS, suggesting an important role of the LDL-associated Lp-PLA(2) in modulating these immune responses. Early atorvastatin treatment prevents both immune responses; however, the clinical significance of this effect remains to be established28. Thus, statin treatment markedly reduced Lp-PLA2 in both plasma and atherosclerotic plaques with attenuation of the local inflammatory response and improved plaque stability 29-33. Effect of direct Lp-PLA2 inhibiton: Darapladib, an inhibitor of Lp-PLA2, when added to lipid lowering therapy such as statins, prevents necrotic core expansion and offers great benefit in the reduction of plaque formation34. Utility of Lp-pla2 in Lipid Lowering Therapy Essay. Darapladib is an orally available, specific inhibitor of LpPLA2 activity and has been shown to reduce lysophosphatidylcholine content and expression of multiple genes associated with macrophage and T-lymphocyte functioning, with considerable decrease in plaque and necrotic core area35. The potential plaque-stabilizing effects of darapladib may represent an important approach in treating atherosclerosis and reducing cardiovascular risk (See figure 4) Therapeutic interpretation of Lp-PLA2 as an inflammatory risk marker: The degree of CAD (0-, 1-, 2- or 3-vessel disease) and plasma LDL cholesterol significantly correlated to Lp-PLA2 levels36. Elevated Lp-PLA2 levels is 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 37. The low biologic fluctuation and high vascular specificity of Lp-PLA2 makes it possible to use a single measurement in clinical decision making, and it also permits clinicians to follow the Lp-PLA2 marker serially38. Lp-PLA2 is a therapeutic target even in post-transplant patients39. Patients with 30-day Lp-PLA2 activity in the highest quintile were at significantly increased risk of recurrent CV events compared with those in the lowest quintile. Lp-PLA2 is not useful for risk stratification when measured early after ACS. At 30 days, Lp-PLA2 activity is significantly lowered with high-dose statin therapy40. Lp-PLA2 is a significant and independent predictor of risk even for recurrent coronary events in post-infarction patients41. Recent study shows emerging evidence from more than 15 prospective studies conducted since 2000, clearly demonstrate the prognostic ability of increased Lp-PLA2 concentrations or elevated activity for risk of future coronary heart disease (CHD) and stroke 48. Utility of Lp-pla2 in Lipid Lowering Therapy Essay.

Future of Lp-PLA2 as a therapeutic target in various disorders in addition to acute coronary syndrome:
A recent prospective study was done to investigate Lp-PLA2 levels in patients with ischemic stroke and severe inflammatory reaction as compared to 38 patients with ischemic stroke without inflammatory reaction and healthy elderly controls. Lp-PLA2 levels were assessed using the diaDexus PLAC test (a noncompetitive ELISA. Patients with ischemic stroke and severe inflammatory reaction presented Lp-PLA2 with high levels more frequently than the healthy controls. Lp-PLA2 is a strong predictor of recurrent stroke risk and of increased risk of dying. The determination of Lp-PLA2 should be used to predict patient risk of cardiovascular disease and stroke. Lp-PLA2 might be used not only for risk stratification of stroke patients, but also as target for treatment42. PAF-AH activity and distribution in women with polycystic ovarian syndrome (PCOS) could contribute to the low-grade chronic inflammation and increased risk of atherosclerosis43. Laboratory of genetic disease and perinatal medicine, conducted a study to investigate a possible association of the polymorphism of PAF-AH gene with the risk of PCOS and to evaluate the effects of the genotype on the activity and distribution of PAFAH. Prevalence of the mutant genotype (GT + TT) was significantly more frequent in patients with PCOS than in control subjects. Genotype (GT + TT) remained a significant predictor for PCOS in prognostic models including age, body mass index, insulin resistance index, triglyceride, HDL and LDL as covariates. The G994T polymorphism in PAFAH gene may be one of the genetic determinants for PCOS 49. A recent data supports an association between deficiency in PAFAH activity and atopic asthma 44. Platelet-activating factor (PAF), which has been implicated in the pathophysiology of inflammation in asthma, is degraded and inactivated by PAF acetylhydrolase (PAFAH. Deficiency of PAFAH is due to a loss-of-function variant (Val279Phe) in the PAFAH gene.50 Inflammation may be a causative factor in congestive heart failure (CHF). In a Cardiovascular Health Study, a prospective observational study demonstrated an association of Lp-PLA2 antigen with risk of future CHF in older people, independent of CHF and coronary risk factors, and partly mediated by coronary disease events45. PAF-AH is been shown to be positively correlated with an increase C-reactive protein in Diabetes type 1 (DM1) patients. PAF-AH appears to be implicated in the development of a chronic inflammation in DM1. This was found by evaluating the concentration of PAF-AH in patients treated with intensive insulin therapy in DM1 46. In a Health Professionals Follow-up Study (HPFS) and Nurses’ Health Study (NHS), it is found the levels of Lp-PLA2 activity were significantly associated with incident CHD among men and women with type 2 diabetes, independent of traditional and inflammatory risk factors 51.

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In summary: Lipid lowering agents especially statins decrease LDL level and inhibit Lp-PLA2, which reduces plaque formation and increases plaque stability due to reduced inflammation and decreased apoptosis of macrophages47. Darapladib, a direct inhibitor of Lp-PLA2, when added to lipid lowering therapy such as statins, offers great benefit through the potential plaque-stabilizing effect. Lp-PLA2 as an inflammatory marker, it is used as therapeutic target of lipid lowering drugs and could be utilized for pre-treatment risk assessment and post-treatment monitoring.
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