CommentaryEffect of hypolipidemic drugs on lipoprotein-associated platelet activating factor acetylhydrolase: Implication for atherosclerosis
Introduction
PAF-AH is an enzyme that exhibits an α/β hydrolase conformation and has broad substrate specificity towards lipid esters containing short acyl chains. Among the various activities, the Ca2+-independent phospholipase A2 activity of PAF-AH has been principally studied. Indeed, PAF-AH has marked preference for phospholipids with short chain moieties at the sn-2 position and, in addition to the potent proinflammatory lipid mediator PAF, it can hydrolyze proinflammatory and proatherogenic oxidized phospholipids [1].
In normolipidemic human plasma PAF-AH is associated mainly with the apoB-containing lipoproteins and primarily with LDL. A small proportion of circulating enzyme activity (less than 20%) is associated with HDL. Within these lipoprotein pools, the enzyme preferentially associates with small-dense LDL and with the very high-density lipoprotein-1 (VHDL-1) subfraction, alternatively denoted as HDL-3c [2]. Among LDL subspecies, the PAF-AH activity in normolipidemic plasma is positively correlated only with the enzyme activity associated with dense LDL subfractions, thus further supporting the preferential association of PAF-AH with small-dense LDL particles [3]. The distribution of PAF-AH between LDL and HDL can be influenced by the presence of lipoprotein (a) (Lp(a)) when plasma levels of this lipoprotein exceed 30 mg/dL [4]. It has been shown that Lp(a) contains several-fold greater PAF-AH activity compared with LDL when assayed at equimolar protein concentrations [4], [5].
The primary sources of circulating PAF-AH constitute cells of hematopoietic origin and primarily macrophages [6], [7]. Although PAF-AH in plasma is associated with lipoproteins, their existence in plasma is not required for the enzyme activity. Since the cells of hematopoietic origin do not secrete lipoproteins, it seems that secretion of PAF-AH occurs independently of the secretion of lipoprotein particles; the enzyme subsequently associates with these particles in plasma. Consistent with this hypothesis, PAF-AH activity in plasma of individuals with HDL deficiency (Tangier disease) is higher than that of normal subjects [8], whereas individuals with abetalipoproteinemia have normal or slightly subnormal PAF-AH activity [9]. However, our recent studies have demonstrated that the lipoprotein metabolism as well as the lipoprotein plasma levels significantly influences the plasma PAF-AH activity. In this brief report, we present our resent results on the effect of hypolipidemic drugs on the plasma- and lipoprotein-associated PAF-AH activity in the most common types of dyslipidemia, primary hypercholesterolemia, combined hyperlipidemia, and primary hypertriglyceridemia.
Section snippets
Effect of hypolipidemic drugs on PAF-AH activity in patients with primary hypercholesterolemia
Patients with primary hypercholesterolemia (Type IIA dyslipidemia) exhibit an elevation of total plasma- and LDL-associated PAF-AH activity whereas the HDL-associated enzyme activity (HDL-PAF-AH) is not significantly altered. The plasma enzyme activity is positively correlated with total plasma cholesterol, LDL-cholesterol, as well as apoB levels. The increase in the LDL-PAF-AH concerns the increase in enzyme activity associated with all LDL particles, i.e. the large, intermediate, and
Effect of hypolipidemic drugs on PAF-AH activity in patients with combined hyperlipidemia
Similar to the results obtained for the total plasma- and LDL-associated PAF-AH activity in patients with primary hypercholesterolemia, are those obtained in patients with combined hyperlipidemia (Type IIB dyslipidemia). However, a significant increase in the subfraction of triglyceride-rich very low-density lipoprotein+intermediate-density lipoprotein (VLDL+IDL), in parallel to the increase in LDL-associated enzyme activity, is also observed in this patient group. This increase contributes to
Effect of fenofibrate on PAF-AH activity in patients with primary hypertriglyceridemia
Like in the other types of dyslipidemia, patients with primary hypertriglyceridemia (Type IV dyslipidemia) exhibit significantly higher plasma PAF-AH activity than normolipidemic volunteers. However, in contrast to Types IIA and IIB dyslipidemic patients, the increased levels of triglyceride-rich lipoproteins may play a key role in this elevation. Indeed, the enzyme activity associated with LDL as well as with individual LDL subspecies, including small-dense LDL, is not altered in primary
Plasma PAF-AH in atherosclerosis: the role of hypolipidemic therapy
PAF-AH may play a significant role in atherogenesis and cardiovascular disease due to its role in the metabolism of bioactive lipids, such as PAF and oxidized phospholipids [1]. However, the role of this enzyme in atherosclerotic disease remains a subject of controversy. Data from the WOSCOPS trial suggest that plasma levels of PAF-AH mass, which mainly reflects the LDL-associated enzyme, represent an independent risk factor for coronary artery disease [18]. In contrast, results from the
Conclusion
Dyslipidemia induces a significant increase in total plasma PAF-AH activity and alters the enzyme distribution between proatherogenic apoB- and antiatherogenic apo AI-containing lipoproteins. The decreased rate of LDL removal from the circulation and the abnormal catabolism of triglyceride-rich lipoproteins play important roles in these abnormalities. Accumulating data indicate that PAF-AH activity associated with HDL particles plays a predominantly antiatherogenic role. By contrast, the role
References (22)
- et al.
Inflammation, bioactive lipids and atherosclerosis: potential roles of a lipoprotein-associated phospholipase A2, platelet activating factor-acetylhydrolase
Atheroscler. Suppl.
(2002) - et al.
Altered distribution of PAF-acetylhydrolase activity between LDL and HDL as a function of the severity of hypercholesterolemia
J. Lipid Res.
(2002) - et al.
PAF-acetylhydrolase activity on Lp(a) before and during Cu2+-induced oxidative modification in vitro
Atherosclerosis
(1996) - et al.
Enhanced association of platelet-activating factor acetylhydrolase with lipoprotein (a) in comparison with low density lipoprotein
J. Biol. Chem.
(1995) - et al.
Cellular source(s) of platelet-activating-factor acetylhydrolase activity in plasma
Biochem. Biophys. Res. Commun.
(1999) - et al.
Human macrophages secrete platelet-activating factor acetylhydrolase
J. Biol. Chem.
(1990) - et al.
The degradation of platelet-activating factor in the plasma of a patient with familial high density lipoprotein deficiency (Tangier disease)
Blood
(1985) - et al.
Determinants of plasma platelet-activating factor acetylhydrolase: heritability and relationship to plasma lipoproteins
J. Lipid Res.
(1997) - et al.
Fenofibrate induces HDL-associated PAF-AH but attenuates enzyme activity associated with apo B-containing lipoproteins
J. Lipid Res.
(2003) - et al.
PPARs, metabolic disease and atherosclerosis
Pharmacol. Res.
(2001)
A prospective evaluation of lipoprotein associated phospholipase A2 levels and the risk of future cardiovascular events in women
J. Am. Coll. Cardiol.
Cited by (48)
Mechanism of oxidized phospholipid-related inflammatory response in vascular ageing
2023, Ageing Research ReviewsEffects of lifestyle counseling and combination lipid-modifying therapy on lipoprotein-associated phospholipase A2 mass concentration
2009, Journal of Clinical LipidologyΤhe role of lipoprotein-associated phospholipase A<inf>2</inf> in atherosclerosis may depend on its lipoprotein carrier in plasma
2009, Biochimica et Biophysica Acta - Molecular and Cell Biology of LipidsRole of Lipoprotein-Associated Phospholipase A<inf>2</inf> in Vascular Disease
2009, Clinical Lipidology: A Companion to Braunwald's Heart Disease