Role of Lipoprotein-Associated Phospholipase A ₂ in Atherosclerosis

Abstract

Abstract-The development of atherosclerotic vascular disease is invariably linked to the formation of bioactive lipid mediators and accompanying vascular inflammation. Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) is an enzyme that is produced by inflammatory cells, co-travels with circulating low-density lipoprotein (LDL), and hydrolyzes oxidized phospholipids in LDL. Its biological role has been controversial with initial reports purporting atheroprotective effects of Lp-PLA 2 thought to be a consequence of degrading platelet-activating factor and removing polar phospholipids in modified LDL. Recent studies, however, focused on pro-inflammatory role of Lp-PLA 2 mediated by products of the Lp-PLA 2 reaction (lysophosphatidylcholine and oxidized nonesterified fatty acids). These bioactive lipid mediators, which are generated in lesion-prone vasculature and to a lesser extent in the circulation (eg, in electronegative LDL), are known to elicit several inflammatory responses. The proinflammatory action of Lp-PLA 2 is also supported by a number of epidemiology studies suggesting that the circulating level of the enzyme is an independent predictor of cardiovascular events, despite some attenuation of the effect by inclusion of LDL, the primary carrier of Lp-PLA 2 , in the analysis. These observations provide a rationale to explore whether inhibiting Lp-PLA 2 activity and consequent interference with the formation of bioactive lipid mediators will abrogate inflammation associated with atherosclerosis, produce favorable changes in intermediate cardiovascular end points (eg, biomarkers, imaging, and endothelial function), and ultimately reduce cardiovascular events in high-risk patients. D espite considerable progress in treating atherosclerotic vascular disease, patients at high risk continue to experience fatal and nonfatal cardiovascular events. Two complementary approaches to this problem have emerged. The first strategy focuses on aggressive control of modifiable risk factors (diabetes, hypertension, dyslipidemia, smoking). Efforts in this direction are justifiable because of the presence of at least 1 conventional risk factor in Ͼ80% patients presenting with acute myocardial infarction and the high societal cost of ineffective prevention. 1-3 Clinical experience suggests no threshold values for implementing corrective therapies in regard to some risk factors in individuals at high risk. 4,5 The second strategy seeks to identify novel treatments that target previously unrecognized mechanisms of atherosclerosis. Despite a wide range of clinical and pathological manifestations of atherosclerotic vascular disease, inflammation is common to all stages of the disease. Studies have linked circulating inflammatory biomarkers with cardiovascular risk, whereas mechanistic investigations have established a pivotal role of blood-borne inflammatory cells and their products in the Original

The inhibition of lipoprotein-associated phospholipase A2 exerts beneficial effects against atherosclerosis in LDLR-deficient mice

“…Thus, the expression of lp-PLA2 at atherosclerotic plaques needs further study. MCP-1, VCAM-1, and ICAM-1 are typical inflammatory cytokines mediating cell adhesion, a crucial step for monocyte migration into lesions [7] . LysoPCs, the product of lp-PAL2, can up-regulate MCP-1 and ICAM-1/VCAM-1 expression in the endothelial cells or vascular smooth muscle cells (VSMCs) [36] .…”

“…3.1.1.47), is a Ca 2+ -independent, 45 kDa secreted protein that associates with lipoproteins and circulates within the plasma in active form [7] . Lp-PLA2 can be up-regulated by the oxidized phospholipids in oxLDL [8] and in turn acts upon those oxidized phospholipids to produce two pro-inflammatory mediators, lysophosphatidylcholines (lysoPCs) and oxidized nonesterified fatty acids (oxNEFAs) [9] .…”

The epidemiology of Lp-PLA2: Distribution and correlation with cardiovascular risk factors in a population-based cohort

“…However, more recent reports suggest the actions of Lp-PLA 2 are proatherogenic (7). In humans, Lp-PLA 2 in circulation is bound predominantly to LDL (8), and oxidative modification to the phospholipid component of LDL provides the substrate for the enzyme (9,10). Lp-PLA 2 acts very rapidly following LDL oxidation to hydrolyze one of the fatty acid moieties (sn-2) of the phospholipid to produce two inflammatory moleculesoxidized nonesterified fatty acids and lysophosphatidylcholine (lysoPC) (7).…”

“…Given that the majority of total body oxidized LDL resides within the intima (versus in circulation), the products of Lp-PLA 2 activity are generated within the vessel wall where the inflammatory processes of atherosclerosis occur. Both oxidized nonesterified fatty acids and lysoPC are highly soluble, diffuse throughout atheroma, and affect the various cell types involved in atherosclerosis (9).…”

Effect of Darapladib on Plasma Lipoprotein-Associated Phospholipase A₂ Activity in Japanese Dyslipidemic Patients, With Exploratory Analysis of a <i>PLA₂G7</i> Gene Polymorphism of Val279Phe

“…The secondary efficacy analysis phospholipids with oxidatively truncated sn-2 chains, lacking enzymatic activity on naturally occurring long-chain fatty acids in phospholipids found in cellular membranes. 6 There are some polymorphisms of the Lp-PLA2 gene (PLA2G7). The Val279Phe (V279F) homogygous mutation (279FF) is the only polymorphism theoretically resulting in no circulating gene product of Lp-PLA2.…”