Skip to main content

Advertisement

SpringerLink
Log in

Sirolimus Therapy Is Associated with Elevation in Circulating PCSK9 Levels in Cardiac Transplant Patients

  • Original Article
  • Published:
Journal of Cardiovascular Translational Research Aims and scope Submit manuscript

Abstract

Sirolimus used in transplantation is often associated with hypercholesterolemia. We measured serum lipid and PCSK9 levels in 51 heart transplant recipients who had their immunosuppressive therapy switched from calcineurin inhibitors to sirolimus. The switch resulted in a 23% increase in LDL cholesterol, and 46% increase in triglycerides and PCSK9 levels increased from 316 ± 105 ng/mL to 343 ± 107 ng/mL (p = 0.04), however the change in PCSK9 levels did not correlate with an increase in lipid levels (p = 0.2). To investigate the mechanism for the variability in the change in PCSK9 levels, lymphoblastoid cell lines were incubated with both sirolimus and everolimus, resulting in a 2–3 fold increase in PCSK9 expression and protein levels in mTOR inhibitor sensitive but not in mTOR inhibitor resistant cell lines. This first in human study demonstrates that sirolimus therapy is associated with elevation in PCSK9 levels which is not associated with sirolimus-induced hypercholesterolemia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

(AA):

African–American

(CNI):

calcineurin inhibitor

(CA):

Caucasian–American

(HCA):

Han Chinese–American

(LCL):

Lymphoblastoid Cell Lines

(PCSK9):

Proprotein convertase subtilisin/kexin Type 9

(SREBP):

sterol regulatory element-binding protein

References

  1. Neuhaus, P., Klupp, J., & Langrehr, J. M. (2001). mTOR inhibitors: an overview. Liver Transplantation, 7(6), 473–484. doi:10.1053/jlts.2001.24645.

    Article  CAS  PubMed  Google Scholar 

  2. Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., et al. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature, 460(7253), 392–395. doi:10.1038/nature08221.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Bak, T., Wachs, M., Trotter, J., Everson, G., Trouillot, T., Kugelmas, M., et al. (2001). Adult-to-adult living donor liver transplantation using right-lobe grafts: results and lessons learned from a single-center experience. Liver Transplantation, 7(8), 680–686. doi:10.1053/jlts.2001.26509.

    Article  CAS  PubMed  Google Scholar 

  4. Brattstrom, C., Wilczek, H., Tyden, G., Bottiger, Y., Sawe, J., & Groth, C. G. (1998). Hyperlipidemia in renal transplant recipients treated with sirolimus (rapamycin). Transplantation, 65(9), 1272–1274.

    Article  CAS  PubMed  Google Scholar 

  5. MacDonald, A. S. (2001). A worldwide, phase III, randomized, controlled, safety and efficacy study of a sirolimus/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts. Transplantation, 71(2), 271–280.

    Article  CAS  PubMed  Google Scholar 

  6. Neff, G. W., Montalbano, M., Slapak-Green, G., Berney, T., Bejarano, P. A., Joshi, A., et al. (2003). A retrospective review of sirolimus (Rapamune) therapy in orthotopic liver transplant recipients diagnosed with chronic rejection. Liver Transplantation, 9(5), 477–483. doi:10.1053/jlts.2003.50119.

    Article  PubMed  Google Scholar 

  7. Raichlin, E., Bae, J. H., Khalpey, Z., Edwards, B. S., Kremers, W. K., Clavell, A. L., et al. (2007). Conversion to sirolimus as primary immunosuppression attenuates the progression of allograft vasculopathy after cardiac transplantation. Circulation, 116(23), 2726–2733. doi:10.1161/CIRCULATIONAHA.107.692996.

    Article  CAS  PubMed  Google Scholar 

  8. Beutner, F., Brendel, D., Teupser, D., Sass, K., Baber, R., Mueller, M., et al. (2012). Effect of everolimus on pre-existing atherosclerosis in LDL-receptor deficient mice. Atherosclerosis, 222(2), 337–343. doi:10.1016/j.atherosclerosis.2012.03.003.

    Article  CAS  PubMed  Google Scholar 

  9. Zhang, D. W., Lagace, T. A., Garuti, R., Zhao, Z., McDonald, M., Horton, J. D., et al. (2007). Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat a of low density lipoprotein receptor decreases receptor recycling and increases degradation. The Journal of Biological Chemistry, 282(25), 18602–18612. doi:10.1074/jbc.M702027200.

    Article  CAS  PubMed  Google Scholar 

  10. Lamming, D. W., & Sabatini, D. M. (2013). A central role for mTOR in lipid homeostasis. Cell Metabolism, 18(4), 465–469. doi:10.1016/j.cmet.2013.08.002.

    Article  CAS  PubMed  Google Scholar 

  11. Ai, D., Chen, C., Han, S., Ganda, A., Murphy, A. J., Haeusler, R., et al. (2012). Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice. Journal of Clinical Investigation, 122(4), 1262–1270. doi:10.1172/jci61919.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jiang, J., Fridley, B. L., Feng, Q., Abo, R. P., Brisbin, A., Batzler, A., et al. (2013). Genome-wide association study for biomarker identification of rapamycin and everolimus using a lymphoblastoid cell line system. Frontiers in Genetics, 4, 166. doi:10.3389/fgene.2013.00166.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Leander, K., Malarstig, A., Van't Hooft, F. M., Hyde, C., Hellenius, M. L., Troutt, J. S., et al. (2016). Circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) predicts future risk of cardiovascular events independently of established risk factors. Circulation, 133(13), 1230–1239. doi:10.1161/circulationaha.115.018531.

    Article  CAS  PubMed  Google Scholar 

  14. Ehninger, D., Neff, F., & Xie, K. (2014). Longevity, aging and rapamycin. Cellular and Molecular Life Sciences, 71(22), 4325–4346. doi:10.1007/s00018-014-1677-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Schulz, R., Schluter, K. D., & Laufs, U. (2015). Molecular and cellular function of the proprotein convertase subtilisin/kexin type 9 (PCSK9). Basic Research in Cardiology, 110(2), 4. doi:10.1007/s00395-015-0463-z.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Tavori, H., Rashid, S., & Fazio, S. (2015). On the function and homeostasis of PCSK9: reciprocal interaction with LDLR and additional lipid effects. Atherosclerosis, 238(2), 264–270. doi:10.1016/j.atherosclerosis.2014.12.017.

    Article  CAS  PubMed  Google Scholar 

  17. Neff, G. W., Montalbano, M., Slapak-Green, G., Meyer, D., Berney, T., Safdar, K., et al. (2003). Sirolimus therapy in orthotopic liver transplant recipients with calcineurin inhibitor related chronic renal insufficiency. Transplantation Proceedings, 35(8), 3029–3031.

    Article  CAS  PubMed  Google Scholar 

  18. Trotter, J. F., Wachs, M. E., Trouillot, T. E., Bak, T., Kugelmas, M., Kam, I., et al. (2001). Dyslipidemia during sirolimus therapy in liver transplant recipients occurs with concomitant cyclosporine but not tacrolimus. Liver Transplantation, 7(5), 401–408. doi:10.1053/jlts.2001.23916.

    Article  CAS  PubMed  Google Scholar 

  19. Arsenault, B. J., Pelletier-Beaumont, E., Almeras, N., Tremblay, A., Poirier, P., Bergeron, J., et al. (2014). PCSK9 levels in abdominally obese men: association with cardiometabolic risk profile and effects of a one-year lifestyle modification program. Atherosclerosis, 236(2), 321–326. doi:10.1016/j.atherosclerosis.2014.07.010.

    Article  CAS  PubMed  Google Scholar 

  20. Lakoski, S. G., Lagace, T. A., Cohen, J. C., Horton, J. D., & Hobbs, H. H. (2009). Genetic and metabolic determinants of plasma PCSK9 levels. Journal of Clininical Endocrinology & Metabolism, 94(7), 2537–2543. doi:10.1210/jc.2009-0141.

    Article  CAS  Google Scholar 

  21. Haas, M. E., Levenson, A. E., Sun, X., Liao, W. H., Rutkowski, J. M., de Ferranti, S. D., et al. (2016). The role of proprotein convertase subtilisin/kexin type 9 in nephrotic syndrome-associated hypercholesterolemia. Circulation, 134(1), 61–72. doi:10.1161/circulationaha.115.020912.

    Article  CAS  PubMed  Google Scholar 

  22. Morrisett, J. D., Abdel-Fattah, G., Hoogeveen, R., Mitchell, E., Ballantyne, C. M., Pownall, H. J., et al. (2002). Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients. Journal of Lipid Research, 43(8), 1170–1180.

    CAS  PubMed  Google Scholar 

  23. Tur, M. D., Garrigue, V., Vela, C., Dupuy, A. M., Descomps, B., Cristol, J. P., et al. (2000). Apolipoprotein CIII is upregulated by anticalcineurins and rapamycin: implications in transplantation-induced dyslipidemia. Transplantation Proceedings, 32(8), 2783–2784.

    Article  CAS  PubMed  Google Scholar 

  24. Liu, J., Ma, K. L., Zhang, Y., Wu, Y., Hu, Z. B., Lv, L. L., et al. (2015). Activation of mTORC1 disrupted LDL receptor pathway: a potential new mechanism for the progression of non-alcoholic fatty liver disease. The International Journal of Biochemistry & Cell Biology, 61, 8–19. doi:10.1016/j.biocel.2015.01.011.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Endocrinology, Mayo Clinic, Rochester, MN, USA

    Vinaya Simha & Pankaj Shah

  2. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, 200 First Street SW, Rochester, MN, 55905, USA

    Sisi Qin, Liewei Wang & Naveen L. Pereira

  3. Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA

    Byron H. Smith & Walter K. Kremers

  4. Department of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Sudhir Kushwaha & Naveen L. Pereira

Authors
  1. Vinaya Simha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sisi Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pankaj Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Byron H. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Walter K. Kremers
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sudhir Kushwaha
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Liewei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Naveen L. Pereira
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Liewei Wang or Naveen L. Pereira.

Ethics declarations

Funding

This study was funded by the Mayo Clinic Transplant Center.

Conflict of Interest

All of the authors report no conflict of interest pertaining to this manuscript.

Ethical Approval

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

Additional information

Associate Editor Craig Stolen oversaw the review of this article

Vinaya Simha and Sisi Qin contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Simha, V., Qin, S., Shah, P. et al. Sirolimus Therapy Is Associated with Elevation in Circulating PCSK9 Levels in Cardiac Transplant Patients. J. of Cardiovasc. Trans. Res. 10, 9–15 (2017). https://doi.org/10.1007/s12265-016-9719-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12265-016-9719-8

Keywords

Search

Navigation