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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1066-1074.)
© 1999 American Heart Association, Inc.

Original Contributions

Depletion of Preß₁LpA1 and LpA4 Particles by Mast Cell Chymase Reduces Cholesterol Efflux From Macrophage Foam Cells Induced by Plasma

Miriam Lee; Arnold von Eckardstein; Leena Lindstedt; Gerd Assmann; Petri T. Kovanen

From the Wihuri Research Institute, Helsinki, Finland (M.L., L.L., P.T.K.); and the Institut für Klinische Chemie und Laboratoriumsmedizin, Zentrallaboratorium. Westfälische Wilhelms-Universität Münster and Institut für Arterioskleroseforschung an der Universität Münster, Germany (A.v.E., G.A.).

Correspondence to Dr Petri T. Kovanen, Wihuri Research Institute, Kalliolinnantie 4, 00140 Helsinki, Finland. E-mail petri.kovanen{at}wri.fi

Abstract—Exposure of the LpA1-containing particles present in HDL₃ and plasma to a minimal degree of proteolysis by the neutral protease chymase from exocytosed rat mast cell granules (granule remnants) leads to a reduction in the high-affinity component of cholesterol efflux from macrophage foam cells. In this study, we demonstrate for the first time, a role for mast cell chymase in the depletion of the lipid-poor minor components of HDL that are specifically involved in reverse cholesterol transport as initial acceptors of cellular cholesterol. Thus, addition of proteolytically active granule remnants or human skin chymase to cholesterol-loaded macrophages of mouse or human origin incubated with human apoA1, ie, a system in which preß₁LpA1 is generated, resulted in a sharp reduction in the high-affinity cholesterol efflux promoted by apoA1. As determined by nondenaturing 2-dimensional polyacrylamide gradient gel electrophoresis, the granule remnants effectively depleted the preß₁LpA1, but not the LpA1, in HDL₃ and in plasma during incubation at 37°C for <1 hour. Incubation of plasma with granule remnants for 1 hour also led to near disappearance of the LpA4–1 and LpA4–2 particles, but did not affect the distribution of the apoA2-containing lipoproteins present in the plasma. We conclude that the reduced ability of granule remnant-treated HDL₃ and granule remnant-treated plasma to induce cholesterol efflux from macrophage foam cells is caused by selective depletion by mast cell chymase of quantitatively minor A1- and A4-containing subpopulations of HDL. Because these particles, ie, preß₁LpA1 and LpA4, are efficient acceptors of cholesterol from cell surfaces, their depletion by mast cells may block the initiation of reverse cholesterol transport in vivo and thereby favor foam cell formation in the arterial intima, the site of atherogenesis.

Key Words: mast cells • reverse cholesterol transport • preß₁LpA1 • LpA4 • chymase • proteolysis

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