Activated mast cells induce endothelial cell apoptosis by a combined action of chymase and tumor necrosis factor-alpha.
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.


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-alpha (TNF-alpha), or with human chymase and TNF-alpha, 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-alpha inhibitors. Chymase avidly degraded both vitronectin (VN) and fibronectin (FN) produced by the cultured RCMECs. In addition, MC releasate inhibited the activation of NF-kappaB (p65) and activated caspase-8 and -9. Moreover, in HCAECs, human chymase and TNF-alpha induced additive levels of apoptosis.


CONCLUSIONS
Activated MCs induce EC apoptosis by multiple mechanisms: chymase inactivates the FAK-mediated cell survival signaling, and TNF-alpha triggers apoptosis. Thus, by inducing EC apoptosis, MCs may contribute to plaque erosion and complications of atherosclerosis.
Heikkilä
Hanna M
HM
Wihuri Research Institute, Kalliolinnantie 4, 00140 Helsinki, Finland.
Lätti
Soili
S
Leskinen
Markus J
MJ
Hakala
Jukka K
JK
Kovanen
Petri T
PT
Lindstedt
Ken A
KA
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D053818:Chymases / Q000378:metabolism*; D003331:Coronary Vessels / Q000166:cytology; D042783:Endothelial Cells / Q000502:physiology*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000502:physiology; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D014409:Tumor Necrosis Factor-alpha; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D053818:Chymases