Abstract 19351: Reduced Proteasome Heterogeneity Augments Cardiac Remodeling

Abstract

The ubiquitin proteasome system regulates cellular function through targeted degradation of signaling and structural proteins. In the mammalian heart, there exist proteasome subpopulations with distinct functionality, conferring the capacity to adjust proteolytic function under physiological and pathological conditions. In fact, the composition of proteasome subpopulations seems to be highly dynamic during cardiac remodeling. However, whether proteasome composition in turn affects myocardial remodeling is not known. Therefore, aim of the study was to determine whether specific proteasome subpopulations impact cardiac remodeling. Analyses of cardiac proteasome assembly during seven day catecholamine treatment of mice demonstrated that the inducible proteasome subunits β1i and β5i were increasingly incorporated in proteasome complexes (up to 50%), whereas the incorporation of constitutive subunits remained unchanged. During the treatment, heart weight to body weight ratio (HW/BW) increased by approx. 50% (6.1 vs 4.1), documenting that the mice developed cardiac hypertrophy. Functional assays of proteasome activities in hypertrophic hearts showed heterogeneous regulation of substrate specificity and turn-over, further indicating a shift in the composition of proteasome subpopulations. Unchallenged mice lacking the subunit β1i and the corresponding proteasome subpopulation are visually indistinguishable from wild-type mice and have a HW/BW ratio of approx. 4.4. Remarkably, catecholamine challenge for seven days induced a more severe cardiac phenotype in those mice with increased HW/BW of approx. 70% (7.6 vs. 4.4). In conclusion, this study demonstrates for the first time that the ubiquitin proteasome system has the capacity to modulate cardiac tissue mass in response to a hypertrophic stimulus via specific proteasome subpopulations, providing a novel mechanism to regulate cardiac remodeling.