© 1995 American Heart Association, Inc.
Articles |
PAF-Degrading Acetylhydrolase Is Preferentially Associated With Dense LDL and VHDL-1 in Human Plasma
Catalytic Characteristics and Relation to the Monocyte-Derived Enzyme
From the Laboratory of Biochemistry, Department of Chemistry, University of Ioannina, Greece (A.D.T., S.-A.P.K), and the Institut National de la Santé et de la Recherche, Unité de Recherches sur les Lipoprotéines et l'Athérogénèse, Hôpital de la Pitié, Paris, France (C.D., M.J.C., E.N.).
Correspondence to Ewa Ninio, INSERM, Unité de Recherches sur les Lipoprotéines et l'Athérogénèse, U-321, Pavillon Benjamin Delessert, Hôpital de la Pitié, 83, Bd de l'Hôpital, 75651 Paris Cedex 13, France.
Abstract In human plasma, platelet activating factor (PAF)–degrading acetylhydrolase (acetylhydrolase) is principally transported in association with LDLs and HDLs; this enzyme hydrolyzes PAF and short-chain forms of oxidized phosphatidylcholine, transforming them into lyso-PAF and lysophosphatidylcholine, respectively. We have examined the distribution, catalytic characteristics, and transfer of acetylhydrolase activity among plasma lipoprotein subspecies separated by isopycnic density gradient ultracentrifugation; the possibility that the plasma enzyme may be partially derived from adherent monocytes has also been evaluated. In normolipidemic subjects with Lp(a) levels <0.1 mg/mL, acetylhydrolase was associated preferentially with small, dense LDL particles (LDL-5; d=1.050 to 1.063 g/mL) and with the very-high-density lipoprotein–1 subfraction (VHDL-1; d=1.156 to 1.179 g/mL), representing 23.9±1.7% and 20.6±3.2%, respectively, of total plasma activity. The apparent Km values for PAF of the enzyme associated with such lipoproteins were 89.7±23.4 and 34.8±4.5 µmol/L for LDL-5 and VHDL-1, respectively: indeed, the Km value for LDL-5 was some 10-fold higher than that of the light LDL-1, LDL-2, and LDL-3 subspecies, whereas the Km of VHDL-1 was some twofold greater than those of the HDL-2 and HDL-3 subspecies. Furthermore, when expressed on the basis of unit plasma volume, the Vmax of the acetylhydrolase associated with LDL-5 was some 150-fold greater than that in LDL-1 (d=1.019 to 1.023 g/mL). No significant differences in the pH dependence of enzyme activity or in sensitivity to protease inactivation, sulfydryl reagents, the serine protease inhibitor Pefabloc, or the PAF antagonist CV 3988 could be detected between apo B–containing and apo A-I–containing lipoprotein particle subspecies. Incubation of LDL-1 (Km=8.4±2.6 µmol/L) and LDL-2 (d=1.023 to 1.029 g/mL; Km=8.4±3.3 µmol/L) subspecies with LDL-5, in which acetylhydrolase had been inactivated by pretreatment with Pefabloc, demonstrated preferential transfer of acetylhydrolase to LDL-5. Acetylhydrolase transferred to LDL-5 from the light LDL subspecies exhibited a Km of 9.4±2.2 µmol/L, a value characteristic of the particle donors. Finally, acetylhydrolase (Km=23.4±7.6 µmol/L) released by adherent human monocytes in culture was found to bind preferentially to small, dense LDL subspecies upon incubation of Pefabloc-inactivated plasma with monocyte supernatant. We conclude that a form of acetylhydrolase with distinct catalytic properties is preferentially associated with small, dense LDL-5 and VHDL-1 particles in human plasma, suggesting that the surface properties of LDL-5 and VHDL-1 particles are distinct from those of other lipoproteins containing either apo B or apo A-I. This hypothesis is consistent with the transfer of active enzyme from the light LDL subspecies to LDL-5, as well as with the preferential binding of monocyte-derived acetylhydrolase to LDL-5. Finally, because the penetration of arterial intima by lipoproteins is inversely proportional to particle size, our data suggest that both small, dense apo B–containing lipoproteins (ie, LDL-5) and small apo A-I–rich lipoproteins (ie, VHDL-1) may play a key anti-inflammatory role in arterial tissue.
Key Words: inflammatory mediators • human blood monocytes • isopycnic density gradient ultracentrifugation • lipoprotein particle subspecies
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