Abstract 1264: Improvement Of Cardiac Remodeling And Contractile Function By Proteasome Inhibition After Myocardial Infarction
Recent evidence shows that inhibition of the proteasome pathway of protein degradation interferes with the development of cardiac hypertrophy upon pressure overload without impairing cardiac contractile function. Here, we tested whether proteasome inhibitors may improve cardiac function and remodeling upon volume overload induced by myocardial infarction (MI) following permanent occlusion of the left anterior descending artery (LAD) in the mouse heart. Two weeks after MI, mice were treated daily with the proteasome inhibitor epoxomicin (Epo, 0.5 mg/kg) or with the vehicle (Veh) for one week (n=5/group). Tissue samples were harvested from the peri-infarct area and compared to samples from shams. Results are shown in the Table⇓. Three weeks after MI, proteasome activity (PA) assessed by fluorogenic assay significantly increased in MI-Veh compared to sham (P<0.01), which was accompanied by a significant (P<0.05) 1.5- to 3-fold up-regulation of components of the 11S (PA28α and β), 19S (Rpn 2 and Rpt 1) and 20S (α6 protein) particles of the proteasome. MI-Veh mice also showed an increase in left ventricle/tibial length (LV/TL) and in myocyte cross-sectional area (MCA) compared to sham, and developed signs of heart failure, including increased lung weight/tibial length (LW/TL) and left ventricular end-diastolic diameter (LVEDD), and decreased ejection fraction (EF). In MI-Epo mice, proteasome activation was abolished, both LV/TL and MCA were smaller, and all the parameters of cardiac function were better preserved when compared to MI-Veh mice. Therefore, proteasome inhibition after volume overload induced by chronic MI inhibits the deleterious effects of remodeling by blocking the progression of hypertrophy and limiting the deterioration of ventricular function, which may be clinically relevant for the treatment of post-ischemic cardiomyopathy.