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


RESULTS
Twenty 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).


CONCLUSIONS
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.
Bugger
Heiko
H
Department of Cardiac Surgery, University of Leipzig Heart Center, Strümpellstr 39, Leipzig 04289, Germany.
Schwarzer
Michael
M
Chen
Dong
D
Schrepper
Andrea
A
Amorim
Paulo A
PA
Schoepe
Maria
M
Nguyen
T Dung
TD
Mohr
Friedrich W
FW
Khalimonchuk
Oleh
O
Weimer
Bart C
BC
Doenst
Torsten
T
D000818:Animals; D001011:Aorta / Q000502:physiology; D004579:Electron Transport; D005227:Fatty Acids / Q000378:metabolism; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D040901:Proteomics; D016601:RNA-Binding Proteins / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000502:physiology; D014661:Vasoconstriction
D005227:Fatty Acids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D014157:Transcription Factors