Pressure overload and neurohumoral activation differentially affect the myocardial proteome.
Treatment with monocrotaline causes pulmonary hypertension in rats. This results in severe pressure overload-induced hypertrophy of the right ventricles, whilst the normally loaded left ventricles do not hypertrophy. Both ventricles are affected by enhanced neuroendocrine stimulation in this model. We analyzed in this model load-induced and catecholamine-induced changes of right and left ventricular proteome by two-dimensional gel electrophoresis, tryptic in-gel digest, and matrix-assisted laser desorption/ionization-time of flight mass spectrometry. All analyzed animals showed right ventricular hypertrophy without signs of heart failure. Changes of 27 proteins in the right and 21 proteins in the left ventricular myocardium were found. Given the hemodynamic features of this animal model, proteome changes restricted to the right ventricle are caused by pressure overload. We describe for the first time a potentially novel pathway (BRAP2/BRCA1) that is involved in myocardial hypertrophy. Furthermore, we demonstrate that increased afterload-induced hypertrophy leads to striking changes in the energy metabolism with down-regulation of pyruvate dehydrogenase (subunit beta E1), isocitrate dehydrogenase, succinyl coenzyme A ligase, NADH dehydrogenase, ubiquinol-cytochrome C reductase, and propionyl coenzyme A carboxylase. These changes go in parallel with alterations of the thin filament proteome (troponin T, tropomyosin), probably associated with Ca(2+) sensitization of the myofilaments. In contrast, neurohumoral stimulation of the left ventricle increases the abundance of proteins relevant for energy metabolism. This study represents the first in-depth analysis of global proteome alterations in a controlled animal model of pressure overload-induced myocardial hypertrophy.
Schott
Peter
P
Department of Cardiology and Respiratory Care, Georg-August-University, Göttingen, Germany. pschott@gwdg.de <pschott@gwdg.de>
Singer
Silke S
SS
Kögler
Harald
H
Neddermeier
Daniel
D
Leineweber
Kirsten
K
Brodde
Otto-Erich
OE
Regitz-Zagrosek
Vera
V
Schmidt
Bernhard
B
Dihazi
Hassan
H
Hasenfuss
Gerd
G
D000595:Amino Acid Sequence; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D002453:Cell Cycle; D017380:Hypertrophy, Right Ventricular; D007526:Isoelectric Point; D008297:Male; D008969:Molecular Sequence Data; D016686:Monocrotaline / Q000378:metabolism; D009124:Muscle Proteins / Q000032:analysis*; D009206:Myocardium / Q000737:chemistry*; D009490:Neurosecretory Systems / Q000502:physiology*; D020543:Proteome / Q000032:analysis*; D051381:Rats; D017208:Rats, Wistar
D009124:Muscle Proteins; D020543:Proteome; D016686:Monocrotaline