title: Proteomic and metabolomic analysis of atrial profibrillatory remodelling in congestive heart failure.
abstract: Congestive heart failure (CHF) leads to atrial structural remodelling and increased susceptibility to atrial fibrillation. The underlying molecular mechanisms are poorly understood. We applied high-throughput proteomic and metabolomic analysis to left-atrial cardiomyocytes and tissues obtained from sham and ventricular-tachypaced (VTP, 240 bpm × 24 h and × 2 weeks) CHF dogs. Protein-extracts were subjected to two-dimensional gel electrophoresis using differential in-gel electrophoresis technology. Differentially expressed (P<0.05) proteins were identified by tandem mass-spectrometry. Cardiac metabolites were assayed with high-resolution NMR spectroscopy. Extensive changes occurred in structural proteins, particularly at 2-week VTP, with desmin and filamin fragmentation suggesting structural damage, which was confirmed by electron-microscopy. Oxidant stress was evidenced by decreased antioxidant proteins (superoxide dismutase and peroxiredoxin) at 2-week VTP. Extensive changes in cardioprotective heat shock proteins (HSPs) occurred, with several proteins increasing rapidly (HSP27, HSP60 and HSP70) and others showing a delayed rise (GRP78, α-B-crystallin, and HSP90). An evolving adaptive response to metabolic stress was suggested by early upregulation of malate dehydrogenase (DH), α-/β-enolase and pyruvate dehydrogenase (α-subunit of E1 component) and delayed downregulation of a host of enzymes, along with extensive metabolomic changes. Early changes in metabolite expression that persisted as CHF developed included increased concentrations of glucose and alanine. ADP/ATP accumulation and alpha-ketoisovalerate depletion at 2-week VTP suggested a combination of metabolic stress and less effective energy utilization, as well as a shift from glycolysis to alpha-ketoacid metabolism. We conclude that VTP-induced CHF causes time-dependent changes in the atrial proteome and metabolome, providing insights into molecular mechanisms contributing to arrhythmogenic atrial remodelling.
authors.affiliation: Department of Cardiac & Vascular Sciences, St. George's University of London, London, UK. adesouza@sgul.ac.uk
authors.forename: Ayesha I
authors.initials: AI
authors.lastname: De Souza
authors.forename: Sophie
authors.initials: S
authors.lastname: Cardin
authors.forename: Robin
authors.initials: R
authors.lastname: Wait
authors.forename: Yuen-Li
authors.initials: YL
authors.lastname: Chung
authors.forename: Meeraa
authors.initials: M
authors.lastname: Vijayakumar
authors.forename: Ange
authors.initials: A
authors.lastname: Maguy
authors.forename: A John
authors.initials: AJ
authors.lastname: Camm
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001281:Atrial Fibrillation / Q000150:complications* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015153:Blotting, Western; D003285:Contractile Proteins / Q000378:metabolism; D004285:Dogs; D055724:Electrophysiological Phenomena; D006333:Heart Failure / Q000150:complications* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006360:Heat-Shock Proteins / Q000378:metabolism; D006439:Hemodynamics; D055432:Metabolomics; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D040901:Proteomics; D057825:Two-Dimensional Difference Gel Electrophoresis
chemical_list: D000975:Antioxidants; D003285:Contractile Proteins; D006360:Heat-Shock Proteins