title: Pilot study identifying myosin heavy chain 7, desmin, insulin-like growth factor 7, and annexin A2 as circulating biomarkers of human heart failure.
abstract: In-depth proteomic analyses offer a systematic way to investigate protein alterations in disease and, as such, can be a powerful tool for the identification of novel biomarkers. Here, we analyzed proteomic data from a transgenic mouse model with cardiac-specific overexpression of activated calcineurin (CnA), which results in severe cardiac hypertrophy. We applied statistically filtering and false discovery rate correction methods to identify 52 proteins that were significantly different in the CnA hearts compared to controls. Subsequent informatic analysis consisted of comparison of these 52 CnA proteins to another proteomic dataset of heart failure, three available independent microarray datasets, and correlation of their expression with the human plasma and urine proteome. Following this filtering strategy, four proteins passed these selection criteria, including myosin heavy chain 7, insulin-like growth factor-binding protein 7, annexin A2, and desmin. We assessed expression levels of these proteins in mouse plasma by immunoblotting, and observed significantly different levels of expression between healthy and failing mice for all four proteins. We verified antibody cross-reactivity by examining human cardiac explant tissue by immunoblotting. Finally, we assessed protein levels in plasma samples obtained from four unaffected and four heart failure patients and demonstrated that all four proteins increased between twofold and 150-fold in heart failure. We conclude that MYH7, IGFBP7, ANXA2, and DESM are all excellent candidate plasma biomarkers of heart failure in mouse and human.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON, Canada; Heart and Stroke/Richard Lewar Centre of Cardiovascular Excellence, Toronto, ON, Canada.
authors.forename: Shaan
authors.initials: S
authors.lastname: Chugh
authors.forename: Maral
authors.initials: M
authors.lastname: Ouzounian
authors.forename: Zhen
authors.initials: Z
authors.lastname: Lu
authors.forename: Shanas
authors.initials: S
authors.lastname: Mohamed
authors.forename: Wenping
authors.initials: W
authors.lastname: Li
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bousette
authors.forename: Peter P
authors.initials: PP
authors.lastname: Liu
authors.forename: Anthony O
authors.initials: AO
authors.lastname: Gramolini
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D016208:Databases, Factual; D003893:Desmin / Q000097:blood*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000097:blood*; D006352:Heart Ventricles / Q000737:chemistry; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000737:chemistry; D018995:Myosin Heavy Chains / Q000097:blood*; D009369:Neoplasms / Q000378:metabolism; D010865:Pilot Projects; D040901:Proteomics
chemical_list: C472822:ANXA2 protein, human; D017306:Annexin A2; D015415:Biomarkers; D003893:Desmin; D018969:Insulin-Like Growth Factor Binding Proteins; C102529:insulin-like growth factor binding protein-related protein 1; D019703:Calcineurin; D018995:Myosin Heavy Chains
keywords: Animal proteomics; Bioinformatics; Plasma; Secreted protein