Chronic pressure overload increased proteasome activity (P<0.05), and proteasome inhibition with epoxomicin completely prevented left ventricular hypertrophy in a mouse model.
Does proteasome inhibition with epoxomicin prevent left ventricular hypertrophy in animal models of chronic pressure overload?
Proteasome activation is required for the development of left ventricular hypertrophy during chronic pressure overload, and its inhibition prevents LVH in preclinical models.
p-value: p=<0.05
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.
Depré et al. (2006) studied Left ventricular hypertrophy. Pressure overload and proteasome inhibition (epoxomicin) vs. Controls / Sham was evaluated on Proteasome expression and activity, and development of left ventricular hypertrophy (p=<0.05). Chronic pressure overload increased proteasome activity (P<0.05), and proteasome inhibition with epoxomicin completely prevented left ventricular hypertrophy in a mouse model.