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(Circulation. 2007;115:2516-2525.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

Perivascular Mast Cells Promote Atherogenesis and Induce Plaque Destabilization in Apolipoprotein E–Deficient Mice

Ilze Bot, PhD^*; Saskia C.A. de Jager, BSc^*; Alma Zernecke, MD, PhD; Ken A. Lindstedt, PhD; Theo J.C. van Berkel, PhD; Christian Weber, MD, PhD; Erik A.L. Biessen, PhD

From the Division of Biopharmaceutics (I.B., S.C.A.d.J., T.J.C.v.B., E.A.L.B.), Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Leiden, the Netherlands; Institute of Molecular Cardiovascular Research (A.Z., C.W.), University Hospital, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany; Wihuri Research Institute (K.A.L.), Helsinki, Finland.

Correspondence to Ilze Bot, PhD, Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, PO Box 9502, Einsteinweg 55, 2333 CC, Leiden, the Netherlands. E-mail i.bot{at}lacdr.leidenuniv.nl

Received August 24, 2006; accepted March 2, 2007.

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.

Methods and 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.

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