Abstract 528: Restricted Proteasome Heterogeneity Promotes Premature Heart Failure and Deterioration of Associated Protein Levels Upon Continuous β-Adrenergic Stimulation

Introduction: The ubiquitin proteasome-system is a main contributor to cellular proteostasis. The dynamic regulation of proteasome composition and function during cardiac remodeling has been of high interest. To what extend discrete proteasome subunits in turn modify cardiac remodeling, is poorly understood. Objective: Aim of the study was to investigate the contribution of the non-essential proteasome subunit low molecular mass peptide 2 (Lmp2) on cardiac function, tissue and proteome upon induced hypertrophic remodeling. Methods & Results: We found induction of cardiac Lmp2 during isoproterenol (Iso)- and TAC-induced remodeling and hypertrophic cardiomyopathy. Unchallenged adult mice congenitally lacking Lmp2 (KO) were indistinguishable from their WT littermates. After 7 days of continuous Iso administration (30 mg/kg/d) though, cardiac function was significantly reduced in Lmp2 KO mice as compared to WT (fractional shortening: -32% vs. WT, p<0.01, n≥9). Interestingly, reduced cardiac function was accompanied by augmented cardiac remodeling as shown by heart weight to body weight ratio, wall thickness, cardiomyocyte cross-sectional area and interstitial collagen content. Cardiac-restricted re-expression of Lmp2 utilizing AAV9-mediated gene transfer rescued cardiac function and restricted remodeling to WT levels, attributing those findings to cardiac Lmp2. Hence, we analyzed the cardiac proteome utilizing 2-D DIGE. Out of approximately 1500 detected protein spots, 114 were showing significant differences upon cardiac remodeling depending on absolute Lmp2 protein expression (p≤0.05). All spots were manually inspected for correct matching across 10 gels. Subsequently, spots were picked with priority on those with the most prominent changes in abundance and identified by mass spectrometry. For example, we found significantly less carbonic anhydrase 2 and manganese superoxide dismutase in the remodeled myocardium of WT compared to Lmp2 KO mice. Conclusions: Cardiac lack of Lmp2 exacerbates cardiac remodeling, which is reflected in the cardiac proteome by deteriorated levels of proteins with a known pivotal role in human cardiac disease.