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Drug-induced macrophage autophagy in atherosclerosis: for better or worse?

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Abstract

Autophagy is a reparative, life-sustaining process by which cytoplasmic components are sequestered in double membrane vesicles and degraded upon fusion with lysosomal compartments. Mice with a macrophage-specific deletion of the essential autophagy gene Atg5 develop plaques with increased apoptosis and oxidative stress as well as enhanced plaque necrosis. This finding indicates that basal autophagy in macrophages is anti-apoptotic and present in atherosclerotic plaques to protect macrophages against various atherogenic stressors. However, autophagy is impaired in advanced stages of atherosclerosis and its deficiency promotes atherosclerosis in part through activation of the inflammasome. Because basal autophagy can be intensified selectively in macrophages by specific drugs such as mammalian target of rapamycin (mTOR) inhibitors or Toll-like receptor 7 (TLR7) ligands, these drugs were recently tested as potential plaque stabilizing compounds. Stent-based delivery of the mTOR inhibitor everolimus promotes a stable plaque phenotype, whereas local administration of the TLR7 ligand imiquimod stimulates inflammation and plaque progression. Therefore, more drugs capable of inducing autophagy should be tested in plaque macrophages to evaluate the feasibility of this approach. Given that drug-induced macrophage autophagy is associated with pro-inflammatory responses due to cytokine release, induction of postautophagic necrosis or activation of phagocytes after clearance of the autophagic corpse, cotreatment with anti-inflammatory compounds may be required. Overall, this review highlights the pros and cons of macrophage autophagy as a drug target for plaque stabilization.

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Acknowledgments

This work was supported by the Fund for Scientific Research (FWO)-Flanders (projects G.0431.11N, G.0448.11N, G.0443.12N and G.0074.12N) and the University of Antwerp. The authors are indebted to Lieve Svensson, Francis Terloo and Dominique De Rijck for excellent technical assistance during transmission electron microscopy.

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Authors and Affiliations

  1. Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium

    Wim Martinet, Inge De Meyer, Dorien M. Schrijvers & Guido R. Y. De Meyer

  2. Antwerp Cardiovascular Center, ZNA Middelheim, Antwerp, Belgium

    Stefan Verheye

  3. Laboratory of Cell Biology and Histology, University of Antwerp, Antwerp, Belgium

    Jean-Pierre Timmermans

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  1. Wim Martinet
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  2. Inge De Meyer
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  3. Stefan Verheye
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  5. Jean-Pierre Timmermans
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  6. Guido R. Y. De Meyer
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Correspondence to Wim Martinet.

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Martinet, W., De Meyer, I., Verheye, S. et al. Drug-induced macrophage autophagy in atherosclerosis: for better or worse?. Basic Res Cardiol 108, 321 (2013). https://doi.org/10.1007/s00395-012-0321-1

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  • DOI: https://doi.org/10.1007/s00395-012-0321-1

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