on October 16, 2006
Published online before print October 16, 2006, doi: 10.1161/CIRCULATIONAHA.106.637827
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Submitted on November 1, 2005
From the Cardiovascular Research Institute (C.D., Q.W., L.Y., N.H., P.P., C.H., L.H., B.G., J.S., D.E.V., S.F.V.), Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, Newark, and Department of Biochemistry (L.C., K.M.), Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway. * To whom correspondence should be addressed. E-mail: vatnersf{at}umdnj.edu.
Background--The adaptation of cardiac mass to hemodynamic overload requires an adaptation of protein turnover, ie, the balance between protein synthesis and degradation. We tested 2 hypotheses: (1) chronic left ventricular hypertrophy (LVH) activates the proteasome system of protein degradation, especially in the myocardium submitted to the highest wall stress, ie, the subendocardium, and (2) the proteasome system is required for the development of LVH. Methods and Results--Gene and protein expression of proteasome subunits and proteasome activity were measured separately from left ventricular subendocardium and subepicardium, right ventricle, and peripheral tissues in a canine model of severe, chronic (2 years) LVH induced by aortic banding and then were compared with controls. Both gene and protein expressions of proteasome subunits were increased in LVH versus control (P<0.05), which was accompanied by a significant (P<0.05) increase in proteasome activity. Posttranslational modification of the proteasome was also detected by 2-dimensional gel electrophoresis. These changes were found specifically in left ventricular subendocardium but not in left ventricular subepicardium, right ventricle, or noncardiac tissues from the same animals. In a mouse model of chronic pressure overload, a 50% increase in heart mass and a 2-fold increase in proteasome activity (both P<0.05 versus sham) were induced. In that model, the proteasome inhibitor epoxomicin completely prevented LVH while blocking proteasome activation. Conclusions--The increase in proteasome expression and activity found during chronic pressure overload in myocardium submitted to higher stress is also required for the establishment of LVH.
Revised on July 24, 2006
Accepted on July 27, 2006
Activation of the Cardiac Proteasome During Pressure Overload Promotes Ventricular Hypertrophy
Christophe Depre MD, PhD,
Key words: heart diseases • hypertrophy • physiology • pressure • stress • proteins
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