title: Sirolimus Therapy Is Associated with Elevation in Circulating PCSK9 Levels in Cardiac Transplant Patients.
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.
authors.affiliation: Division of Endocrinology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Vinaya
authors.initials: V
authors.lastname: Simha
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, 200 First Street SW, Rochester, MN, 55905, USA.
authors.forename: Sisi
authors.initials: S
authors.lastname: Qin
authors.affiliation: Division of Endocrinology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Shah
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
authors.forename: Byron H
authors.initials: BH
authors.lastname: Smith
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
authors.forename: Walter K
authors.initials: WK
authors.lastname: Kremers
authors.affiliation: Department of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Kushwaha
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, 200 First Street SW, Rochester, MN, 55905, USA. wang.liewei@mayo.edu.
authors.forename: Liewei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, 200 First Street SW, Rochester, MN, 55905, USA. pereira.naveen@mayo.edu.|Department of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. pereira.naveen@mayo.edu.
authors.forename: Naveen L
authors.initials: NL
authors.lastname: Pereira
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D045744:Cell Line, Tumor; D008078:Cholesterol, LDL / Q000097:blood; D057915:Drug Substitution; D005260:Female; D016027:Heart Transplantation / Q000009:adverse effects; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000139:chemically induced / Q000175:diagnosis; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D000071449:Proprotein Convertase 9 / Q000097:blood*; D020123:Sirolimus / Q000009:adverse effects / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D008078:Cholesterol, LDL; D007166:Immunosuppressive Agents; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D020123:Sirolimus
keywords: Cardiac transplant; Hypercholesterolemia; PCSK9; Sirolimus; mTOR inhibitors