Mast cell chymase inhibition reduces atherosclerotic plaque progression and improves plaque stability in ApoE-/- mice.
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.
Bot
Ilze
I
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
Bot
Martine
M
van Heiningen
Sandra H
SH
van Santbrink
Peter J
PJ
Lankhuizen
Inge M
IM
Hartman
Peter
P
Gruener
Sabine
S
Hilpert
Hans
H
van Berkel
Theo J C
TJ
Fingerle
Jürgen
J
Biessen
Erik A L
EA
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
D001057:Apolipoproteins E; D007210:Indoleacetic Acids; D009281:Naphthalenes; D011480:Protease Inhibitors; D012333:RNA, Messenger; C557082:RO 5066852; D011973:Receptors, LDL; D053818:Chymases