Abstract 20950: An Intrinsic Mechanism for a Gain in Proteasome Activity Preserving Cardiac Function

Cardiac remodeling and heart failure are characterized by misaligned adaptations in protein synthesis and degradation, harboring the therapeutic potential for interventional harmonization. Partial inhibition of protein degradation via the ubiquitin-proteasome system was reported to reduce acute hypertrophic remodeling as well as recover systolic function. The studies are suggestive of an inadequate gain in proteasome activity, contributing to cardiac remodeling and heart failure. Aim was to identify a common mechanism promoting proteasome activity during cardiac remodeling and heart failure and to test whether it contributes to the pathogenesis. Incorporation of the inducible proteasome subunit Lmp2 has been described to increase proteasome activity. In fact, it is increasingly expressed and incorporated in proteasome complexes during isoproterenol-induced hypertrophic remodeling, which is associated with a gain in proteasome activity. We found that Lmp2 is also increasingly expressed upon transverse aortic constriction and in a murine model of familial hypertrophic cardiomyopathy. Knock-out (KO) of Lmp2 in mice increased the caspase-like proteasome activity by 19% (n=5, p In conclusion, a gain in proteasome activity during acute cardiac remodeling is not entirely maladaptive. At least in part, it is dependent on Lmp2, controlling remodeling and preserving cardiac function.