Pathophysiological Role and Clinical Significance of Lipoprotein-Associated Phospholipase A₂ (Lp-PLA₂) Bound to LDL and HDL

Abstract

Lipoprotein-associated phospholipase A2 (Lp-PLA2), also named as platelet-activating factor (PAF)-acetylhydrolase, exhibits a Ca²⁺-independent phospholipase A2 activity and catalyzes the hydrolysis of the ester bond at the sn-2 position of PAF and oxidized phospholipids (oxPL). These phospholipids are formed under oxidative and inflammatory conditions, and may play important roles in atherogenesis. The vast majority of plasma Lp-PLA2 mass binds to low-density lipoprotein (LDL) while a smaller amount is associated with high-density lipoprotein (HDL). Lp-PLA2 is also bound to lipoprotein (a) [Lp(a)], very low-density lipoprotein (VLDL) and remnant lipoproteins. Several lines of evidence suggest that the role of plasma Lp-PLA2 in atherosclerosis may depend on the type of lipoprotein particle with which this enzyme is associated. Data from large Caucasian population studies have supported plasma Lp-PLA2 (primarily LDL-associated Lp-PLA2) as a cardiovascular risk marker independent of, and additive to, traditional risk factors. On the contrary, the HDL-associated Lp-PLA2 may express antiatherogenic activities and is also independently associated with lower risk for cardiac death. The present review presents data on the biochemical and enzymatic properties of Lp-PLA2 as well as its structural characteristics that determine the association with LDL and HDL. We also critically discuss the possible pathophysiological and clinical significance of the Lp- PLA2 distribution between LDL and HDL in human plasma, in view of the results of prospective epidemiologic studies on the association of Lp-PLA2 with future cardiovascular events as well the recent studies that evaluate the possible effectiveness of specific Lp-PLA2 inhibitors in reducing residual cardiovascular risk.

Lipoprotein-associated phospholipase A₂ activity is increased in patients with definite familial hypercholesterolemia compared with other forms of hypercholesterolemia

“…This difference in assay procedure could also explain why we found a negative correlation with HDL-C despite about 30% of Lp-PLA2 being carried by HDL particles 31 . Several lines of evidence suggest that the Lp-PLA2 roles in atherosclerosis pathophysiology may depend on the type of lipoprotein particles with which it is associated to 32 . It seems that only LDL-associated Lp-PLA2 exerts pro-inflammatory activity while HDL-associated Lp-PLA2 seems to have an anti-atherogenic role 33 .…”

Lipoprotein‐associated phospholipase A2: The story continues

“…HDL‐associated Lp‐PLA2 is highly acknowledged to be anti‐inflammatory, while LDL‐associated Lp‐PLA2 is proinflammatory; however, the underlying mechanisms have yet to be elucidated. Alterations in the distribution of Lp‐PLA2 between LDL and HDL were detected in patients with various diseases, including atherosclerosis, dyslipidemias, DM, and PCOS . However, the clinical consequences of these alterations were inadequately determined .…”

“…Lipoprotein‐associated phospholipase A2 (Lp‐PLA2) belongs to group VII of the PLA2 superfamily, which currently comprises of six types and is divided into 16 unique groups . This enzyme is principally secreted by macrophages and circulates in the blood in the form of a complex with low‐density lipoprotein (LDL) and high‐density lipoprotein (HDL) . Lp‐PLA2 was originally named plasma platelet‐activating factor acetylhydrolase (pPAF‐AH), due to its hydrolytic action on platelet‐activating factor (PAF) .…”

“…In the past decade, a number of reviews have been published with respect to the structure, genetic aspects, biological roles, disease implications, and specific inhibitors of Lp‐PLA2 . In addition, Lp‐PLA2 has been reviewed as a part of the PLA2 superfamily or PAF‐AHs .…”

Comparison of serum Lp‐PLA2 levels in ischemic stroke patients with H‐type hypertension or non‐H‐type hypertension

“…In the blood circulation, Lp‐PLA2 primarily binds to LDL‐C and HDL‐C . Lp‐PLA2 can generate the pro‐inflammatory molecules lysophosphatidylcholine and oxidized free fatty acids by hydrolyzing phospholipids of LDL‐C and HDL‐C, and these pro‐inflammatory molecules promote ischemic stroke …”