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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:309.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

Activated Mast Cells Induce Endothelial Cell Apoptosis by a Combined Action of Chymase and Tumor Necrosis Factor-

Hanna M. Heikkilä; Soili Lätti; Markus J. Leskinen; Jukka K. Hakala; Petri T. Kovanen; Ken A. Lindstedt

From the Wihuri Research Institute, Helsinki, Finland.

Correspondence to Ken A. Lindstedt, Wihuri Research Institute, Kalliolinnantie 4, 00140 Helsinki, Finland. E-mail ken.lindstedt{at}wri.fi

Abstract

Objective— Activated mast cells (MCs) induce endothelial cell (EC) apoptosis in vitro and are present at sites of plaque erosions in vivo. To further elucidate the role of MCs in endothelial apoptosis and consequently in plaque erosion, we have studied the molecular mechanisms involved in MC-induced EC apoptosis.

Methods and Results— Primary cultures of rat cardiac microvascular ECs (RCMECs) and human coronary artery ECs (HCAECs) were treated either with rat MC releasate (ie, mediators released on MC activation), rat chymase and tumor necrosis factor- (TNF-), or with human chymase and TNF-, respectively. MC releasate induced RCMEC apoptosis by inactivating the focal adhesion kinase (FAK) and Akt-dependent survival signaling pathway, and apoptosis was partially inhibited by chymase and TNF- inhibitors. Chymase avidly degraded both vitronectin (VN) and fibronectin (FN) produced by the cultured RCMECs. In addition, MC releasate inhibited the activation of NF-B (p65) and activated caspase-8 and -9. Moreover, in HCAECs, human chymase and TNF- induced additive levels of apoptosis.

Conclusions— Activated MCs induce EC apoptosis by multiple mechanisms: chymase inactivates the FAK-mediated cell survival signaling, and TNF- triggers apoptosis. Thus, by inducing EC apoptosis, MCs may contribute to plaque erosion and complications of atherosclerosis.

Activated mast cells are present in the subendothelial space of coronary atheromas, colocalize with plaque erosions and parietal microthrombi, and induce endothelial cell apoptosis in vitro by a combined action of chymase and TNF-. Thus, activated mast cells may contribute to plaque erosion with the progression of atherosclerosis and its complications.

Key Words: atherosclerosis • mast cell • apoptosis • chymase • plaque erosion