title: Mast cell chymase inhibition reduces atherosclerotic plaque progression and improves plaque stability in ApoE-/- mice.
abstract: OBJECTIVE
  mast cells have been shown to accumulate in the adventitia of human atherosclerotic plaques and were recently demonstrated by us to contribute to plaque progression and instability. In this study, we investigated whether selective inhibition of mast cell chymases would affect the lesion development and stability.
  
  
  RESULTS
  the protease inhibitor RO5066852 appeared to be a potent inhibitor of chymase activity in vitro and ex vivo. With this inhibitor, we provide three lines of evidence that chymase inhibition can prevent many pro-atherogenic activities. First, oral administration of RO5066852 reduced spontaneous atherosclerosis in the thoracic aorta of apoE(-/-) mice. Second, chymase inhibition prevented the accelerated plaque progression observed in apoE(-/-) mice that were exposed to repetitive episodes of systemic mast cell activation. Furthermore, RO5066852 enhanced lesional collagen content and reduced necrotic core size. Third, RO5066852 treatment almost completely normalized the increased frequency and size of intraplaque haemorrhages observed in apoE(-/-) mice after acute perivascular mast cell activation in advanced atherosclerosis.
  
  
  CONCLUSIONS
  our data indicate that chymase inhibition can inhibit pro-atherogenic and plaque destabilizing effects which are associated with perivascular mast cell activation. Our study thus identifies pharmacological chymase inhibition as a potential therapeutic modality for atherosclerotic plaque stabilization.
authors.affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands. i.bot@lacdr.leidenuniv.nl
authors.forename: Ilze
authors.initials: I
authors.lastname: Bot
authors.forename: Martine
authors.initials: M
authors.lastname: Bot
authors.forename: Sandra H
authors.initials: SH
authors.lastname: van Heiningen
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van Santbrink
authors.forename: Inge M
authors.initials: IM
authors.lastname: Lankhuizen
authors.forename: Peter
authors.initials: P
authors.lastname: Hartman
authors.forename: Sabine
authors.initials: S
authors.lastname: Gruener
authors.forename: Hans
authors.initials: H
authors.lastname: Hilpert
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: van Berkel
authors.forename: Jürgen
authors.initials: J
authors.lastname: Fingerle
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D053818:Chymases / Q000037:antagonists & inhibitors* / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D007210:Indoleacetic Acids / Q000494:pharmacology*; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009281:Naphthalenes / Q000494:pharmacology*; D058226:Plaque, Atherosclerotic / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D011480:Protease Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D007210:Indoleacetic Acids; D009281:Naphthalenes; D011480:Protease Inhibitors; D012333:RNA, Messenger; C557082:RO 5066852; D011973:Receptors, LDL; D053818:Chymases