Proteomic and metabolomic analysis of atrial profibrillatory remodelling in congestive heart failure.
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.
De Souza
Ayesha I
AI
Department of Cardiac & Vascular Sciences, St. George's University of London, London, UK. adesouza@sgul.ac.uk
Cardin
Sophie
S
Wait
Robin
R
Chung
Yuen-Li
YL
Vijayakumar
Meeraa
M
Maguy
Ange
A
Camm
A John
AJ
Nattel
Stanley
S
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
D000975:Antioxidants; D003285:Contractile Proteins; D006360:Heat-Shock Proteins