title: Serum biomarkers reveal long-term cardiac injury in isoproterenol-treated African green monkeys.
abstract: The assessment of cardiac toxicity is a major challenge in both drug development and clinical trials, and numerous marketed pharmaceuticals have been removed from the market due to unpredicted cardiac effects. Serum troponins are widely used indicators of cardiac injury; however, they are short-lived and have not been validated in preclinical animal models. In this study, we have used filter-aided sample preparation (FASP) and tandem mass tag (TMT) labeling to investigate serum protein alterations in isoproterenol-treated African green monkeys. Our results showed that the combination of FASP and TMT labeling provided highly reproducible and efficient sample preparation, which enables us to identify and quantify serum proteins with high confidence. We focused on the proteins that exhibit long-term alteration upon isoproterenol injection and discovered nine proteins exhibiting significant changes at 48 and 72 h postdosing. We further chose three proteins, serum amyloid A (SAA), frutose biphosphate aldolase A (FBAA), and fetuin A, for validation using enzyme-linked immunosorbent assay (ELISA). The serum concentration of SAA showed a ∼ 50 fold increase, while concentration of FBAA and fetuin A exhibited a significant decrease accompanying isoproterenol-induced cardiotoxicity. This work provides valuable insights for multimarker evaluation of long-term cardiac injury.
authors.affiliation: Center for Advanced Drug Research, SRI International , Harrisonburg, Virginia 22801, United States.
authors.forename: Yashu
authors.initials: Y
authors.lastname: Liu
authors.forename: Toufan
authors.initials: T
authors.lastname: Parman
authors.forename: Bridget
authors.initials: B
authors.lastname: Schneider
authors.forename: Benben
authors.initials: B
authors.lastname: Song
authors.forename: Amit K
authors.initials: AK
authors.lastname: Galande
authors.forename: Dave
authors.initials: D
authors.lastname: Anderson
authors.forename: Jon
authors.initials: J
authors.lastname: Mirsalis
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood*; D001798:Blood Proteins / Q000032:analysis / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004797:Enzyme-Linked Immunosorbent Assay; D005634:Fructose-Bisphosphate Aldolase / Q000097:blood; D006321:Heart / Q000187:drug effects*; D007545:Isoproterenol / Q000009:adverse effects*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D015203:Reproducibility of Results; D000685:Serum Amyloid A Protein / Q000032:analysis / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D060749:alpha-2-HS-Glycoprotein / Q000032:analysis / Q000378:metabolism
chemical_list: D015415:Biomarkers; D001798:Blood Proteins; D000685:Serum Amyloid A Protein; D060749:alpha-2-HS-Glycoprotein; D005634:Fructose-Bisphosphate Aldolase; D007545:Isoproterenol