Degradation of phospholipid transfer protein (PLTP) and PLTP-generated pre-beta-high density lipoprotein by mast cell chymase impairs high affinity efflux of cholesterol from macrophage foam cells.
Human atherosclerotic lesions contain mast cells filled with the neutral protease chymase. Here we studied the effect of human chymase on (i) phospholipid transfer protein (PLTP)-mediated phospholipid (PL) transfer activity, and (ii) the ability of PLTP to generate pre-beta-high density lipoprotein (HDL). Immunoblot analysis of PLTP after incubation with chymase for 6 h revealed, in addition to the original 80-kDa band, four specific proteolytic fragments of PLTP with approximate molecular masses of 70, 52, 48, and 31 kDa. This specific pattern of PLTP degradation remained stable for at least 24 h of incubation with chymase. Such proteolyzed PLTP had reduced ability (i) to transfer PL from liposome donor particles to acceptor HDL(3) particles, and (ii) to facilitate the formation of pre-beta-HDL. However, when PLTP was incubated with chymase in the presence of HDL(3), only one major cleavage product of PLTP (48 kDa) was generated, and PL transfer activity was almost fully preserved. Moreover, chymase effectively depleted the pre-beta-HDL particles generated from HDL(3) by PLTP and significantly inhibited the high affinity component of cholesterol efflux from macrophage foam cells. These results suggest that the mast cells in human atherosclerotic lesions, by secreting chymase, may prevent PLTP-dependent formation of pre-beta-HDL particles from HDL(3) and so impair the anti-atherogenic function of PLTP.
Lee
Miriam
M
Wihuri Research Institute, Kalliolinnantie 4, FIN-00140 Helsinki, Finland.
Metso
Jari
J
Jauhiainen
Matti
M
Kovanen
Petri T
PT
D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D053818:Chymases; D005487:Foam Cells / Q000378:metabolism*; D053442:High-Density Lipoproteins, Pre-beta; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008407:Mast Cells / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D049294:Phospholipid Transfer Proteins; D010743:Phospholipids / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*
D002352:Carrier Proteins; D053442:High-Density Lipoproteins, Pre-beta; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; D049294:Phospholipid Transfer Proteins; D010743:Phospholipids; D002784:Cholesterol; D012697:Serine Endopeptidases; D053818:Chymases