Article

Mast cell chymase induces smooth muscle cell apoptosis by disrupting NF-κB-mediated survival signaling

Wihuri Research Institute, Kalliolinnantie 4, FI-00140 Helsinki, Finland.
Experimental Cell Research (Impact Factor: 3.25). 06/2006; 312(8):1289-98. DOI: 10.1016/j.yexcr.2005.12.033
Source: PubMed

ABSTRACT

Chymase released from activated mast cells induces apoptosis of vascular smooth muscle cells (SMCs) in vitro by degrading the pericellular matrix component fibronectin, so causing disruption of focal adhesion complexes and Akt dephosphorylation, which are necessary for cell adhesion and survival. However, the molecular mechanisms of chymase-mediated apoptosis downstream of Akt have remained elusive. Here, we show by means of RT-PCR, Western blotting, EMSA, immunocytochemistry and confocal microscopy, that chymase induces SMC apoptosis by disrupting NF-kappaB-mediated survival signaling. Following chymase treatment, the translocation of active NF-kappaB/p65 to the nucleus was partly abolished and the amount of nuclear p65 was reduced. Pretreatment of SMCs with chymase also inhibited LPS- and IL-1beta-induced nuclear translocation of p65. The chymase-induced degradation of p65 was mediated by active caspases. Loss of NF-kappaB-mediated transactivation resulted in downregulation of bcl-2 mRNA and protein expression, leading to mitochondrial swelling and release of cytochrome c. The apoptotic process involved activation of both caspase 9 and caspase 8. The results reveal that, by disrupting the NF-kappaB-mediated survival-signaling pathway, activated chymase-secreting mast cells can mediate apoptosis of cultured arterial SMCs. Since activated mast cells colocalize with apoptotic SMCs in vulnerable areas of human atherosclerotic plaques, they may participate in the weakening and rupture of atherosclerotic plaques.

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    • "In mast cell-deficient mice, there is no detectable chymase mRNA, suggesting that at baseline in the absence of any stress the mast cell is the primary source of chymase [3]. In addition to converting angiotensin I (Ang I) to Ang II [3], [4], chymase directly degrades fibronectin [5], activates matrix metalloproteinases (MMPs) [6], [7], [8], and initiates apoptosis in cardiomyocytes through disruption of the focal adhesion complex in vitro [9], [10]. Based on amino acid sequence homology, chymase is divided into two groups, α and β. "
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