Abstract 9073: Profiling of Metabolic Remodeling in Rat Model of Pressure Overload Induced Early Systolic Dysfunction and in Progression to Overt Systolic Heart Failure

Abstract

Introduction: We have previously shown left ventricular (LV) structural and hemodynamic differences in two models of rat pressure overload induced moderate remodeling and early systolic dysfunction (MOD) and overt systolic heart failure (SHF). The MOD and SHF phenotypes develop 8 weeks post ascending aortic banding via a vascular clip, area of 2 mm 2 and 1.5 mm 2 , respectively. Hypothesis: Metabolic remodeling play significant role in the development of MOD and SHF phenotypes, but is more evident in SHF than MOD. Methods: Shotgun proteomics and phospho-(p)-proteomics and non-targeted metabolomics analysis was performed in LV myocardium tissue from Sham, MOD and SHF using liquid chromatography mass spectrometry (LC-MS); n=3 biological samples per group. Raw proteomics, p-proteomics and metabolomics MS data were uploaded into Qlucore bioinformatics software for statistical analysis and data visualization. Statistically analyzed data were then uploaded into Ingenuity Pathway Analysis bioinformatics software for data validation and assessment of highly enriched canonical pathways related to metabolism that were up or down-regulated in MOD and SHF relative to Sham. Some of the proteomics and p-proteomics data were validated by immunoblotting. Results: Canonical pathways of oxidative phosphorylation, fatty acid β-oxidation, Kreb’s cycle, branched-chain amino acid and amino acid (Glutamine and Tryptophan) degradation were downregulated in MOD vs Sham and were further downregulated in SHF vs MOD. Whilst glycogen degradation and glucose degradation were upregulated in MOD and SHF vs Sham, but more so in MOD than SHF. Metabolomics data revealed that long chain and very long chain acyl-carnitines were decreased in abundance in MOD and SHF relative to Sham, while short and medium chain acyl-carnitines were decreased in abundance in SHF only. Moreover, Isoleucine degradation and glycolysis decreased and Taurine biosynthesis increased in SHF vs MOD. p-Proteomics data showed mild decrease in protein kinase A (PKA) and AMPK signaling in MOD vs Sham, which were more profoundly decreased in SHF than MOD. Conclusion: The interplay between PKA and AMPK signaling play an important role in metabolic remodeling and transitioning from MOD to SHF phenotype.