Abstract 12762: Cardiac Hypertrophy is Associated With Discordant Protein Turnover in Metabolic Pathways

Abstract

Introduction: Cardiac hypertrophy preceding heart failure is commonly associated with disrupted protein homeostasis. How alterations in protein temporal stability and turnover may contribute to disease phenotypes is poorly understood, due in part to difficulties in measuring protein half-life in the heart in vivo. Hypothesis: We hypothesize that disrupted proteostasis contributes to cardiac remodelling in part by altering the turnover rates of enzymes necessary to maintain cardiac functions. Method: We developed a technology platform combining stable isotope mass spectrometry, computational modelling and a systems genetics model to investigate the dynamics of proteome remodelling in cardiac hypertrophy over six inbred mouse strains. The mice (C57BL/6J, DBA/2J, CE/J, A/J, FVB/NJ, BALB/cJ) were selected from a panel of >100 strains for their contrasting responses to isoproterenol, which permits regression modelling of proteome dynamics over phenotypic responses. Results: We completed 1,404 LC-MS/MS experiments to quantify the turnover and abundance of 3,227 proteins from 127,648 data series. We performed weighted correlation network analysis to classify the protein data into 15 modules in an unsupervised manner. Strikingly, we found that protein interaction partners and functionally related proteins share synchronous turnover, and that coordinated turnover networks overlapped with metabolic pathways. Regression models show the turnover rate of glycolytic enzymes is a positive predictor of the severity of cardiac hypertrophy in the mouse strains (r: 0.58 - 0.80), whereas the turnover of fatty acid oxidation proteins (e.g., ACAT1, ACAD10, HADHA/B, DBT, ACAA2) is negatively correlated (r: -0.66 - -0.89). Conclusion: Our study provides the first clues on the association between cardiac remodelling and protein turnover networks, and uncovered potential disease drivers that evade steady-state gene expression analysis.