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Article Addendum
z-VAD-fmk-Induced Non-Apoptotic Cell Death of Macrophages: Possibilities and Limitations for Atherosclerotic Plaque Stabilization
Wim Martinet, Dorien M. Schrijvers, Arnold G. Herman, Guido R.Y. De Meyer
volume 2 | issue 4
October/November/December 2006Pages: 308 - 310
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Macrophages play a pivotal role in atherosclerotic plaque destabilization in contrast to smooth muscle cells (SMCs). As a consequence, removal of macrophages from plaques via selective induction of cell death represents a promising approach to stabilize non-obstructive, rupture-prone atherosclerotic lesions. However, the mechanisms to initiate cell death in macrophages but not in other cell types of the plaque, in particular SMCs, are unknown. Recently, we have shown that the pan-caspase inhibitor z-VAD-fmk induces autophagy and necrotic cell death in J774A.1 and RAW264.7 macrophages as well as in IFN-gamma primed primary mouse peritoneal macrophages, but not in vascular SMCs or C2C12 myoblasts. The different sensitivity to z-VAD-fmk is largely based on differential expression of receptor-interacting protein 1 (RIP1). This finding suggests that caspase inhibition activates RIP1 which in turn initiates autophagy, although other explanations should be taken into account. z-VAD-fmk-treated J774A.1 macrophages overexpress and secrete several chemokines and cytokines, including TNFa. The combination of z-VAD-fmk and TNFalpha, but not TNFalpha alone, induces SMCs necrosis. In this regard, z-VAD-fmk is detrimental and not beneficial for atherosclerotic plaque stability due to stimulation of inflammatory responses and indirect induction of SMC death. Future work is needed to determine the mechanism(s) that selectively trigger nonapoptotic cell death in plaque macrophages without evoking inflammation and SMC death.
Addendum to:
Macrophages but not Smooth Muscle Cells Undergo Benzyloxycarbonyl-Val-Ala-DL-Asp(O-methyl)-fluoromethylketone-Induced Non-Apoptotic Cell Death Depending on Receptor-Interacting Protein 1 Expression: Implications for the Stabilization of Macrophage-Rich Atherosclerotic Plaques
W. Martinet, G.R.Y. De Meyer, J.-P. Timmermans, A.G. Herman, M.M. Kockx
J Pharmacol Exp Ther 2006; 317:1356-64
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.