doi: 10.1161/CIRCULATIONAHA.105.547257
(Circulation. 2005;112:e108-e109.)
© 2005 American Heart Association, Inc.
Correspondence |
Letter Regarding Article by Winkler et al, "Platelet-Activating Factor Acetylhydrolase Activity Indicates Angiographic Coronary Artery Disease Independently of Systemic Inflammation and Other Risk Factors: The Ludwigshafen Risk and Cardiovascular Health Study"
INSERM U525, Université P.M. Curie, Faculté de Médecine Pitié-Salpêtrière, Paris, France
Winkler and colleagues1 have published an epidemiological study on the platelet-activating factor acetylhydrolase (PAF-AH) and coronary artery disease. The authors stated erroneously in the Introduction that PAF-AH releases arachidonic acid, a precursor of eicosanoid production including prostaglandins and leukotrienes. On the basis of this assumption, the authors suggest in the Discussion that PAF-AH possesses proinflammatory functions within the atherosclerotic plaque because it is preferentially associated with small dense LDL2; the latter may thus contribute to atherogenesis by functioning as a reservoir of the essential substrate (ie, the arachidonate-containing phosphatidylcholine), and the source of crucial enzyme activity necessary for prostaglandin synthesis. In addition, the authors emphasize that this concept would confer an active role on PAF-AH in atherogenesis rather than it being a mere risk marker.
Actually, PAF-AH, in contrast to other classical phospholipases A2 that are interfacial enzymes, does not cleave the sn-2 long-chain fatty acids such as arachidonic acid, which contains as many as 20 carbons. PAF-AH acts on its substrates in the aqueous phase, and for this reason it degrades essentially water-soluble phospholipids3 including PAF, in this case by hydrolyzing its acetate moiety (2 carbons) in the sn-2 position of glycerol.4 PAF-AH also degrades the short-chain sn-2-analogues of phosphatidylcholine up to 5 carbons5 or medium-length oxidized chains up to 9 carbons.3 These molecules are nonenzymatically generated on oxidation of phosphatidylcholine containing an sn-2 polyunsaturated fatty acyl. Of importance, the polyunsaturated fatty acyl is directly truncated into the short-chain oxidized moieties, among which the 1-pamitoyl- 2-oxovaleroyl-sn-glycero-3-phosphocholine (POVPC; 5 carbons) is one of the major compounds of minimally modified LDL and atherosclerotic lesions6 and is an equally good substrate for PAF-AH.7 For these reasons, PAF-AH was proposed as being a protective mechanism against the accumulation of biologically active oxidized phospholipids in the sites of inflammation, and its exact role in atherogenesis is still under evaluation.8
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1. Winkler K, Winkelmann BR, Scharnagl H, Hoffmann MM, Grawitz AB, Nauck M, Bohm BO, Marz W. Platelet-activating factor acetylhydrolase activity indicates angiographic coronary artery disease independently of systemic inflammation and other risk factors: the Ludwigshafen Risk and Cardiovascular Health Study. Circulation. 2005; 111: 980–987.
2. Tselepis AD, Dentan C, Karabina SA, Chapman MJ, Ninio E. PAF-degrading acetylhydrolase is preferentially associated with dense LDL and VHDL-1 in human plasma. Catalytic characteristics and relation to the monocyte-derived enzyme. Arterioscler Thromb Vasc Biol. 1995; 15: 1764–1773.
3. Min JH, Jain MK, Wilder C, Paul L, Apitz-Castro R, Aspleaf DC, Gelb MH. Membrane-bound plasma platelet activating factor acetylhydrolase acts on substrate in the aqueous phase. Biochemistry. 1999; 38: 12935–12942.[CrossRef][Medline] [Order article via Infotrieve]
4. Blank ML, Lee TC, Fitzgerald V, Snyder F. A specific acetylhydrolase for 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine (a hypotensive and platelet-activating lipid). J Biol Chem. 1981; 256: 175–178.
5. Wardlow ML, Cox CP, Meng KE, Greene DE, Farr RS. Substrate specificity and partial characterization of the PAF-acylhydrolase in human serum that rapidly inactivates platelet-activating factor. J Immunol. 1986; 136: 3441–3446.[Abstract]
6. Subbanagounder G, Leitinger N, Schwenke DC, Wong JW, Lee H, Rizza C, Watson AD, Faull KF, Fogelman AM, Berliner JA. Determinants of bioactivity of oxidized phospholipids. Specific oxidized fatty acyl groups at the sn-2 position. Arterioscler Thromb Vasc Biol. 2000; 20: 2248–2254.
7. Stremler KE, Stafforini DM, Prescott SM, Zimmerman GA, McIntyre TM. An oxidized derivative of phosphatidylcholine is a substrate for the platelet-activating factor acetylhydrolase from human plasma. J Biol Chem. 1989; 264: 5331–5334.
8. Ninio E. Phospholipid mediators in the vessel wall: involvement in atherosclerosis. Curr Opin Clin Nutr Metab Care. 2005; 8: 123–131.[Medline] [Order article via Infotrieve]
Department of Medicine, University of Freiburg, Freiburg, Germany
Cardiology Group Frankfurt-Sachsenhausen, Frankfurt, Germany
Clinical Institute of Medical and Chemical Laboratory Diagnostics, University of Graz, Graz, Austria
Department of Medicine, Division of Endocrinology and Diabetes, University of Ulm, Ulm, Germany
We thank Dr Nino for commenting on the role of platelet-activating factor acetylhydrolase (PAF-AH) in coronary artery disease (CAD). As outlined by the author, PAF-AH does not act by an interfacial mechanism. The active site of PAF-AH is located toward the aqueous phase and specificity is merely a function of substrate solubility in an aqueous environment.1 Hence, PAF-AH shows preference to short-chain "hydrophilic" fatty acids, and one important function of PAF-AH is to degrade PAF and proinflammatory oxidized phospholipids. Epidemiological evidence is overwhelming, however, that PAF-AH is clinically associated with increased CAD risk.2,3 According to our preliminary data, the risk conferred by PAF-AH appears to be alleviated by the use of aspirin, which would be compatible with an active role of PAF-AH in atherogenesis delivering substrate to the cyclooxygenase (COX) pathway.
We can only speculate about possible mechanisms turning the antiatherogenic function of PAF-AH in plasma into a proatherogenic within the atheromateous plaque. The plaque provides a hydrophobic environment and may not adequately be described by the terms "aqueous" or "nonaqueous." It cannot completely be ruled out that within the hydrophobic environment of the plaque PAF-AH may hydrolyze even long-chain phospholipids. Furthermore, an indirect contribution of PAF-AH to atherogenesis also appears conceivable. Proinflammatory activity may be mediated by the release of products that have a proatherogenic (signaling) function itself. In general, we completely agree with Dr Nino that PAF-AH may possess a dual pro- and antiatherogenic role, depending on the concentration and availability of substrates.4 We expect future data to elucidate the mechanisms by which PAF-AH may contribute to increased CAD risk.
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1. Min JH, Jain MK, Wilder C, Paul L, Apitz-Castro R, Aspleaf DC, Gelb MH. Membrane-bound plasma platelet activating factor acetylhydrolase acts on substrate in the aqueous phase. Biochemistry. 1999; 38: 12935–12942.[CrossRef][Medline] [Order article via Infotrieve]
2. Packard CJ, O’Reilly DS, Caslake MJ, McMahon AD, Ford I, Cooney J, Macphee CH, Suckling KE, Krishna M, Wilkinson FE, Rumley A, Lowe GD. Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group. N Engl J Med. 2000; 343: 1148–1155.
3. Winkler K, Abletshauser C, Friedrich I, Hoffmann MM, Wieland H, Marz W. Fluvastatin slow-release lowers PAF-AH activity: a placebo controlled trial in patients with type 2 diabetes. J Cin Endocrinol Metab. 2004; 89: 1153–1159.
4. Ninio E. Phospholipid mediators in the vessel wall: involvement in atherosclerosis. Curr Opin Clin Nutr Metab Care. 2005; 8: 123–131.[Medline] [Order article via Infotrieve]
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