Macrophages but not smooth muscle cells undergo benzyloxycarbonyl-Val-Ala-DL-Asp(O-Methyl)-fluoromethylketone-induced nonapoptotic cell death depending on receptor-interacting protein 1 expression: implications for the stabilization of macrophage-rich atherosclerotic plaques

The Journal of Pharmacology and Experimental Therapeutics
Wim MartinetM M Kockx

Abstract

Several lines of evidence suggest that macrophages play a key role in atherosclerotic plaque destabilization and rupture. Therefore, selective removal of macrophages from plaques via pharmacological therapy could 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 J774A.1 and RAW264.7 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, necrosis also occurred, and the number of necrotic cells rapidly increased during z-VAD-fmk treatment. Primary mouse peritoneal macrophages were resistant to z-VAD-fmk-mediated cell death, but unlike SMCs, they underwent z-VAD-fmk-mediated necrosis after pretreatment with interferon-gamma. Further evidence indicated that the expression level of receptor-interac...Continue Reading

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Citations

Feb 22, 2008·Proceedings of the National Academy of Sciences of the United States of America·Claudia MackWolfram Brune
Jan 7, 2010·Journal of Cardiovascular Pharmacology·Valerie CroonsGuido R Y De Meyer
May 21, 2008·Current Atherosclerosis Reports·Wim Martinet, Guido R Y De Meyer
Aug 9, 2008·Toxicology and Applied Pharmacology·Lucy M ElphickGeorge E N Kass
Feb 13, 2007·Trends in Cardiovascular Medicine·Wim MartinetGuido R Y De Meyer
Mar 23, 2011·British Journal of Pharmacology·Wim MartinetGuido R Y De Meyer
Dec 30, 2014·British Journal of Pharmacology·Cécile Vindis
Nov 22, 2007·Trends in Molecular Medicine·Wim MartinetGuido R Y De Meyer
Feb 14, 2009·Circulation Research·Wim Martinet, Guido R Y De Meyer
Dec 1, 2006·The Journal of Pharmacology and Experimental Therapeutics·Valerie CroonsGuido R Y De Meyer
May 4, 2017·Immunological Reviews·Wulf Tonnus, Andreas Linkermann

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