Proteomic remodelling of mitochondrial oxidative pathways in pressure overload-induced heart failure

Heiko Bugger, Michael Schwarzer, Dong Chen, Andrea Schrepper, Paulo A. Amorim, Maria Schoepe, T. Dung Nguyen, Friedrich W. Mohr, Oleh Khalimonchuk, Bart C. Weimer, Torsten Doenst

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Abstract

Aims Impairment in mitochondrial energetics is a common observation in animal models of heart failure, the underlying mechanisms of which remain incompletely understood. It was our objective to investigate whether changes in mitochondrial protein levels may explain impairment in mitochondrial oxidative capacity in pressure overload-induced heart failure. Methods and resultsTwenty weeks following aortic constriction, Sprague-Dawley rats developed contractile dysfunction with clinical signs of heart failure. Comparative mitochondrial proteomics using label-free proteome expression analysis (LC-MS/MS) revealed decreased mitochondrial abundance of fatty acid oxidation proteins (six of 11 proteins detected), increased levels of pyruvate dehydrogenase subunits, and upregulation of two tricarboxylic acid cycle proteins. Regulation of mitochondrial electron transport chain subunits was variable, with downregulation of 53 of proteins and upregulation of 25 of proteins. Mitochondrial state 3 respiration was markedly decreased independent of the substrate used (palmitoyl-carnitine -65, pyruvate -75, glutamate -75, dinitrophenol -82; all P < 0.05), associated with impaired mitochondrial cristae morphology in failing hearts. Perfusion of isolated working failing hearts showed markedly reduced oleate (-68; P < 0.05) and glucose oxidation (-64; P < 0.05). Conclusion Pressure overload-induced heart failure is characterized by a substantial defect in cardiac oxidative capacity, at least in part due to a mitochondrial defect downstream of substrate-specific pathways. Numerous changes in mitochondrial protein levels have been detected, and the contribution of these to oxidative defects and impaired cardiac energetics in failing hearts is discussed.

Original languageEnglish (US)
Pages (from-to)376-384
Number of pages9
JournalCardiovascular research
Volume85
Issue number2
DOIs
StatePublished - Jan 1 2010

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Keywords

  • Chronic heart failure
  • Metabolism
  • Mitochondria
  • Pressure overload
  • Proteomic remodelling

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Bugger, H., Schwarzer, M., Chen, D., Schrepper, A., Amorim, P. A., Schoepe, M., Nguyen, T. D., Mohr, F. W., Khalimonchuk, O., Weimer, B. C., & Doenst, T. (2010). Proteomic remodelling of mitochondrial oxidative pathways in pressure overload-induced heart failure. Cardiovascular research, 85(2), 376-384. https://doi.org/10.1093/cvr/cvp344