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Abstract no.: 2
Caspase inhibitor z‐VAD‐fmk induces nonapoptotic cell death in macrophages but not in smooth muscle cells: an opportunity to stabilize atherosclerotic plaques?
Author(s) -
Martinet W.,
De Meyer G.R.Y.,
Herman A.G.,
Kockx M.M.
Publication year - 2006
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/j.1472-8206.2006.00420_2.x
Subject(s) - programmed cell death , necroptosis , necrosis , microbiology and biotechnology , biology , apoptosis , tumor necrosis factor alpha , autophagy , geldanamycin , caspase , cell culture , cancer research , immunology , heat shock protein , biochemistry , genetics , gene , hsp90
Several lines of evidence suggest that macrophages play a key role in atherosclerotic plaque destabilization and rupture. Selective removal of macrophages from plaques via pharmacological therapy could therefore represent a promising approach to stabilize ‘vulnerable’, rupture‐prone lesions. Yet, how macrophages can be eliminated from plaques without influencing other cell types, including smooth muscle cells (SMCs), is unknown. In the present study, we report that benzyloxycarbonyl‐Val‐Ala‐DL‐Asp(O‐methyl)‐fluoromethylketone (z‐VAD‐fmk), a caspase inhibitor with broad specificity, induces nonapoptotic cell death of macrophages, but not of SMCs. Cell death was characterized by bulk degradation of long‐lived proteins, processing of microtubule associated protein light chain 3, and cytoplasmic vacuolization, which are all markers of autophagy. However, also necrosis occurred and the number of necrotic cells rapidly increased during z‐VAD‐fmk treatment. Western blots revealed that receptor interacting protein 1 (RIP1) is less abundantly expressed in SMCs as compared with macrophages, which may explain the different sensitivity to z‐VAD‐fmk. Selective degradation of RIP1 in macrophages by geldanamycin protected cells against z‐VAD‐fmk induced death, whereas overexpression of RIP1 in SMCs stimulated z‐VAD‐fmk mediated cell death. Importantly, upon z‐VAD‐fmk treatment macrophages overexpressed and secreted several chemokines and cytokines, including tumor necrosis factor‐α (TNFα). The combination of z‐VAD‐fmk and TNFα but not TNFα alone, induced SMCs necrosis via a mechanism that required RIP1 expression. These results suggest that z‐VAD‐fmk, despite its selective cell death inducing capacity, would be detrimental for the stability of atherosclerotic plaques due to enlargement of the necrotic core, stimulation of inflammatory responses and indirect induction of SMC death.