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The Effect of Proprotein Convertase Subtilisin Kexin Type 9 Inhibitors on Circulating Endothelial Progenitor Cells in Patients with Cardiovascular Disease

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Abstract

Purpose

Circulating endothelial progenitor cells (cEPCs) are vital to vascular repair by re-endothelialization. We aimed to explore the effect of proprotein convertase subtilisin kexin type 9 inhibitors (PCSK9i) on cEPCs hypothesizing a possible pleiotropic effect.

Methods

Patients with cardiovascular disease (CVD) were sampled for cEPCs at baseline and following the initiation of PCSK9i. cEPCs were assessed using flow cytometry by the expression of CD34(+)/CD133(+) and vascular endothelial growth factor receptor (VEGFR)-2(+), and by the formation of colony-forming units (CFUs) and production of VEGF.

Results

Our cohort included 26 patients (median age 68 (IQR 63, 73) years; 69% male). Following 3 months of treatment with PCSK9i and a decline in low-density lipoprotein cholesterol levels (153 (IQR 116, 176) to 56 (IQR 28, 72) mg/dl), p < 0.001), there was an increase in CD34(+)/CD133(+) and VEGFR-2(+) cell levels (0.98% (IQR 0.37, 1.55) to 1.43% (IQR 0.90, 4.51), p = 0.002 and 0.66% (IQR 0.22, 0.99) to 1.53% (IQR 0.73, 2.70), p = 0.05, respectively). Functionally, increase in EPCs-CFUs was microscopically evident following treatment with PCSK9i (1 CFUs (IQR 0.0, 1.0) to 2.5 (IQR 1.5, 3), p < 0.001) with a concomitant increase in EPC’s viability as demonstrated by an MTT assay (0.15 (IQR 0.11, 0.19) to 0.21 (IQR 0.18, 0.23), p < 0.001). VEGF levels increased following PCSK9i treatment (57 (IQR 18, 24) to 105 (IQR 43, 245), p = 0.006).

Conclusions

Patients with CVD treated with PCSK9i demonstrate higher levels of active cEPCs, reflecting the promotion of endothelial repair. These findings may represent a novel mechanism of action of PCSK9i.

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Data Availability

Data will be made available by the corresponding author upon request.

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Funding

This study was supported by an unrestricted research grant from AMGEN pharmaceutical company (Protocol #20197006).

Author information

Authors and Affiliations

  1. Department of Cardiology, Rabin Medical Center, 39 Jabotinsky St., 49100, Petah Tikva, Israel

    Osnat Itzhaki Ben Zadok, Aviv Mager, Ran Kornowski & Alon Eisen

  2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Osnat Itzhaki Ben Zadok, Aviv Mager, Dorit Leshem-Lev, Ran Kornowski & Alon Eisen

  3. Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel

    Dorit Leshem-Lev

  4. Department of Cardiology, Assuta Ashdod Medical Center, Ashdod, Israel

    Eli Lev

  5. Faculty of Medicine, Ben-Gurion University, Beersheba, Israel

    Eli Lev

Authors
  1. Osnat Itzhaki Ben Zadok
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  2. Aviv Mager
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  3. Dorit Leshem-Lev
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  4. Eli Lev
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  5. Ran Kornowski
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  6. Alon Eisen
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Contributions

A.E., E.L., and D.L.L. contributed to the study conception and design. Material preparation, data collection, and analysis were performed by O.I.B.Z. and D.L.L. The first draft of the manuscript was written by O.I.B.Z and all authors commented on previous versions of the manuscript. A.E., E.L., D.L.L., A.M., and R.K. read and approved the final manuscript.

Corresponding author

Correspondence to Osnat Itzhaki Ben Zadok.

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The authors declare that they have no conflict of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Itzhaki Ben Zadok, O., Mager, A., Leshem-Lev, D. et al. The Effect of Proprotein Convertase Subtilisin Kexin Type 9 Inhibitors on Circulating Endothelial Progenitor Cells in Patients with Cardiovascular Disease. Cardiovasc Drugs Ther 36, 85–92 (2022). https://doi.org/10.1007/s10557-020-07119-1

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  • DOI: https://doi.org/10.1007/s10557-020-07119-1

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