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

  • Angelos D. Karagiannis
  • Martin Liu
  • Peter P. Toth
  • Shijia Zhao
  • Devendra K. Agrawal
  • Peter Libby
  • Yiannis S. Chatzizisis
Vascular Biology (J. Hamilton, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Vascular Biology


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.


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.


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


Compliance with Ethical Standards

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.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Angelos D. Karagiannis
    • 1
  • Martin Liu
    • 1
  • Peter P. Toth
    • 2
  • Shijia Zhao
    • 1
  • Devendra K. Agrawal
    • 3
  • Peter Libby
    • 4
  • Yiannis S. Chatzizisis
    • 1
  1. 1.Cardiovascular Biology and Biomechanics Laboratory, Cardiovascular DivisionUniversity of Nebraska Medical CenterOmahaUSA
  2. 2.CGH Medical Center, Sterling, IL, and Ciccarone Center for the Prevention of Heart DiseaseJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Department of Clinical and Translational ScienceCreighton University School of MedicineOmahaUSA
  4. 4.Cardiovascular Division, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA

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