In cardiovascular research, the ubiquitin-proteasome system (UPS) has gained major importance, because preserving proteasome function reduces the severity or even prevents cardiac disease phenotypes in animal models. However, the regulation of proteasome function in cardiac disease is poorly understood. In this study, the impact of b-adrenergic signaling on proteasome function was analyzed. Chronic increase of sympathetic activity promotes the pathogenesis of cardiac diseases. We discovered a partial dysfunction of proteasomes in murine hypertrophic hearts (heart weight to body weight ratio: +50%) after 7 days catecholamine treatment (30mg isoproterenol/kg/day). Proteasomes are a heterogenic group of multi-protein complexes with at least six distinct activities. Decreased activities were measured for 20S proteasomes (-40%). However, 26S proteasomes almost doubled their activities in hypertrophic hearts. Chronic sympathetic stimulation desensitizes b-adrenergic signaling and lowers the intracellular pool of cAMP. Remarkably, lost 20S proteasome activities could be rescued by cAMP treatment (up to 56% recovered), whereas 26S proteasomes remained unaffected by cAMP. Inhibition of cAMP dependent protein kinase A (PKA) disrupted the rescue of proteasome function by cAMP treatment. Augmented 26S proteasome function in hypertrophic hearts was associated with increased 26S proteasome assembly and an abnormally reduced cytosolic pool of 26S proteasome substrates (-44%). Thus, the results indicate an overcompensation of 26S proteasome function for 20S proteasome failure. Several proteins participating in b-adrenergic signaling are degraded by the UPS. Here, we demonstrate for the first time that the sympathetic system regulates proteasome function in cardiac remodeling through a coupled positive and negative feedback loop.