Perivascular mast cells promote atherogenesis and induce plaque destabilization in apolipoprotein E-deficient mice.
BACKGROUND
Mast cells are major effector cells in allergy and host defense responses. Their increased number and state of activation in perivascular tissue during atherosclerosis may point to a role in cardiovascular disorders. In the present study, we investigated the contribution of perivascular mast cells to atherogenesis and plaque stability in apolipoprotein E-deficient mice.


RESULTS
We show here that episodes of systemic mast cell activation during plaque progression in mice leads to robust plaque expansion. Targeted activation of perivascular mast cells in advanced plaques sharply increases the incidence of intraplaque hemorrhage, macrophage apoptosis, vascular leakage, and CXCR2/VLA-4-mediated recruitment of leukocytes to the plaque. Importantly, treatment with the mast cell stabilizer cromolyn does prevent all the adverse phenomena elicited by mast cell activation.


CONCLUSIONS
This is the first study to demonstrate that mast cells play a crucial role in plaque progression and destabilization in vivo. We propose that mast cell stabilization could be a new therapeutic approach to the prevention of acute coronary syndromes.
Bot
Ilze
I
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, PO Box 9502, Einsteinweg 55, 2333 CC, Leiden, The Netherlands. i.bot@lacdr.leidenuniv.nl
de Jager
Saskia C A
SC
Zernecke
Alma
A
Lindstedt
Ken A
KA
van Berkel
Theo J C
TJ
Weber
Christian
C
Biessen
Erik A L
EA
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D017209:Apoptosis / Q000187:drug effects; D002199:Capillary Permeability; D002340:Carotid Artery Diseases / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured / Q000187:drug effects / Q000473:pathology; D002634:Chemotaxis, Leukocyte; D004205:Cromolyn Sodium / Q000494:pharmacology / Q000627:therapeutic use*; D004140:Dinitrophenols / Q000633:toxicity; D018450:Disease Progression; D006470:Hemorrhage / Q000209:etiology; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000150:complications / Q000235:genetics; D007249:Inflammation / Q000473:pathology; D039041:Integrin alpha4beta1 / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D023063:Receptors, Interleukin-8B / Q000502:physiology; D012710:Serum Albumin, Bovine / Q000633:toxicity; D053802:Tryptases / Q000494:pharmacology
D001057:Apolipoproteins E; D004140:Dinitrophenols; D039041:Integrin alpha4beta1; D023063:Receptors, Interleukin-8B; C034638:dinitrophenyl-bovine serum albumin; D012710:Serum Albumin, Bovine; D053802:Tryptases; D004205:Cromolyn Sodium