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Pleiotropic Anti-atherosclerotic Effects of PCSK9 Inhibitors From Molecular Biology to Clinical Translation

Current Atherosclerosis Reports volume 20, Article number: 20 (2018) Cite this article

Abstract

Purpose of Review

Clinical trials with PCSK9 inhibitors have shown a robust decrease in plasma LDL levels and a significant reduction in the incidence of cardiovascular atherosclerotic events. However, the role of PCSK9 in atherosclerosis is not well investigated and it remains unclear whether PCSK9 inhibition has direct, LDL-independent, anti-atherosclerotic effects. This review outlines the molecular pathways and targets of PCSK9 in atherosclerosis and summarizes the experimental and clinical data supporting the anti-atherosclerotic (pleiotropic) actions of PCSK9 inhibitors.

Recent Findings

PCSK9 is expressed by various cell types that are involved in atherosclerosis (e.g., endothelial cell, smooth muscle cell, and macrophage) and is detected inside human atherosclerotic plaque. Preclinical studies have shown that inhibition of PCSK9 can attenuate atherogenesis and plaque inflammation.

Summary

Besides increasing plasma LDL, PCSK9 appears to promote the initiation and progression of atherosclerosis. Inhibition of PCSK9 may confer atheroprotection that extends beyond its lipid-lowering effects.

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Authors and Affiliations

  1. Cardiovascular Biology and Biomechanics Laboratory, Cardiovascular Division, University of Nebraska Medical Center, 982265 Nebraska Medical Center, Omaha, NE, 68198, USA

    Angelos D. Karagiannis, Martin Liu, Shijia Zhao & Yiannis S. Chatzizisis

  2. CGH Medical Center, Sterling, IL, and Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Peter P. Toth

  3. Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE, USA

    Devendra K. Agrawal

  4. Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Peter Libby

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  1. Angelos D. Karagiannis
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  2. Martin Liu
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  3. Peter P. Toth
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  4. Shijia Zhao
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  5. Devendra K. Agrawal
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  7. Yiannis S. Chatzizisis
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Correspondence to Yiannis S. Chatzizisis.

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Conflict of Interest

Angelos D. Karagiannis, Martin Liu, Shijia Zhao, Devendra K. Agrawal, and Yiannis S. Chatzizisis declare no conflicts of interest. Peter P. Toth declares personal fees from Regeneron, personal fees from Amgen, and personal fees from Sanofi, outside the submitted work. Peter Libby declares unpaid consultation to Amgen, Esperion Therapeutics, and Sanofi-Regeneron, outside the submitted work.

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Karagiannis, A.D., Liu, M., Toth, P.P. et al. Pleiotropic Anti-atherosclerotic Effects of PCSK9 Inhibitors From Molecular Biology to Clinical Translation. Curr Atheroscler Rep 20, 20 (2018). https://doi.org/10.1007/s11883-018-0718-x

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  • DOI: https://doi.org/10.1007/s11883-018-0718-x

Keywords

  • Proprotein convertase subtilisin/kexin 9
  • Atherosclerosis
  • PCSK9 inhibitors
  • Pleiotropic effects
  • Anti-atherosclerotic effects
  • Evolocumab
  • Alirocumab
  • Inclisiran