title: Mast cell tryptase degrades HDL and blocks its function as an acceptor of cellular cholesterol.
abstract: 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.
authors.affiliation: Wihuri Research Institute, Helsinki, Finland.
authors.forename: Miriam
authors.initials: M
authors.lastname: Lee
authors.forename: Christian P
authors.initials: CP
authors.lastname: Sommerhoff
authors.forename: Arnold
authors.initials: A
authors.lastname: von Eckardstein
authors.forename: Frank
authors.initials: F
authors.lastname: Zettl
authors.forename: Hans
authors.initials: H
authors.lastname: Fritz
authors.forename: Petri T
authors.initials: PT
authors.lastname: Kovanen
mesh_terms: 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
chemical_list: 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