Mast cell tryptase degrades HDL and blocks its function as an acceptor of cellular cholesterol.
OBJECTIVE
In human atherosclerotic lesions, degranulated mast cells are found in the vicinity of macrophage foam cells. Mast cell granules contain tryptase, a tetrameric serine protease requiring glycosaminoglycans for stabilization. No endogenous inhibitors have been described for tryptase, and the physiological functions of the enzyme are poorly understood. Here, we investigated the effects of human tryptase on the integrity of high density lipoprotein (HDL)3 and on its ability to release cholesterol from cultured mouse macrophage foam cells.


RESULTS
Incubation of HDL3 with tryptase led to degradation of its apolipoproteins. Tryptase predominantly degraded a quantitatively minor subfraction of HDL3 that is lipid poor, exhibits electrophoretic pre-beta mobility, and contains either apolipoprotein A-I or apolipoprotein A-IV as its sole apolipoprotein. Moreover, tryptase caused functional changes in HDL3 by destroying its ability to promote high-affinity efflux of cholesterol from macrophage foam cells, ie, the pre-beta-HDL-dependent component of the process. Human aortic proteoglycans increased the ability of tryptase to proteolyze HDL3, suggesting that the proteoglycan-rich extracellular matrix of the arterial intima provides an appropriate environment for the extracellular actions of tryptase.


CONCLUSIONS
By depleting pre-beta-HDL, mast cell tryptase may impair the initial step of reverse cholesterol transport and will then favor cellular accumulation of cholesterol during atherogenesis.
Lee
Miriam
M
Wihuri Research Institute, Helsinki, Finland.
Sommerhoff
Christian P
CP
von Eckardstein
Arnold
A
Zettl
Frank
F
Fritz
Hans
H
Kovanen
Petri T
PT
D000818:Animals; D001011:Aorta / Q000737:chemistry; D016632:Apolipoprotein A-I / Q000378:metabolism; D001693:Biological Transport, Active; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005109:Extracellular Matrix / Q000737:chemistry / Q000201:enzymology; D005487:Foam Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008075:Lipoproteins, HDL / Q000037:antagonists & inhibitors / Q000378:metabolism; D053440:Lipoproteins, HDL3; D008407:Mast Cells / Q000737:chemistry* / Q000201:enzymology*; D051379:Mice; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism* / Q000502:physiology*; D053802:Tryptases; D017539:Tunica Intima / Q000737:chemistry / Q000166:cytology
D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D008075:Lipoproteins, HDL; D053440:Lipoproteins, HDL3; D020033:Protein Isoforms; D011509:Proteoglycans; C509190:Tpsb2 protein, mouse; D002784:Cholesterol; D012697:Serine Endopeptidases; C509222:Tpsab1 protein, mouse; D053802:Tryptases