Comparative proteomic analysis of mouse models of pathological and physiological cardiac hypertrophy, with selection of biomarkers of pathological hypertrophy by integrative proteogenomics

To determine fundamental characteristics of pathological cardiac hypertrophy, protein expression profiles in two widely accepted models of cardiac hypertrophy (swimming-trained mouse for physiological hypertrophy and pressure-overload-induced mouse for pathological hypertrophy) were compared using a label-free quantitative proteomics approach. Among 3955 proteins (19,235 peptides, false-discovery rate < 0.01) identified in these models, 486 were differentially expressed with a log2 fold difference ≥ 0.58, or were detected in only one hypertrophy model (each protein from 4 technical replicates, p < .05). Analysis of gene ontology biological processes and KEGG pathways identified cellular processes enriched in one or both hypertrophy models. Processes unique to pathological hypertrophy were compared with processes previously identified in cardiac-hypertrophy models. Individual proteins with differential expression in processes unique to pathological hypertrophy were further confirmed using the results of previous targeted functional analysis studies. Using a proteogenomic approach combining transcriptomic and proteomic analyses, similar patterns of differential expression were observed for 23 proteins and corresponding genes associated with pathological hypertrophy. A total of 11 proteins were selected as early-stage pathological-hypertrophy biomarker candidates, and the results of western blotting for five of these proteins in independent samples confirmed the patterns of differential expression in mouse models of pathological and physiological cardiac hypertrophy.