Abstract 531: A Lack in Endogenous Proteasome Regulation Provokes Exacerbated Cardiac Remodeling and Premature Heart Failure Following Catecholamine Challenge

Introduction: Cardiac remodeling is associated with a dynamic regulation of the ubiquitin-proteasome system. Our previous studies revealed cardiac induction of the non-essential proteasome subunit low molecular mass peptide 2 (Lmp2) as an early feature of beta-adrenoreceptor overstimulation, as present in chronic human heart disease. However, the impact of Lmp2 upregulation on the progress of cardiac remodeling has not been characterized in detail so far. Objective: Aim of the study was to monitor the contribution of Lmp2 to cardiac remodeling in a mouse model of beta-adrenoceptor overstimulation. Methods & Results: Unchallenged adult mice congenitally lacking Lmp2 (KO) showed no cardiac abnormality including systolic and diastolic function or morphology. After 7 days of continuous isoproterenol administration (30 mg/kg/d using subcutaneous osmotic mini-pumps), both fractional shortening and active diastolic filling of the left ventricle were significantly reduced (by 32%) in Lmp2 KO mice as compared to wildtype littermates (p<0.01, n≥9). Cardiomyocyte-specific adeno-associated virus serotype 9-mediated transfer of the gene encoding Lmp2 rescued cardiac function in Lmp2 KO mice, suggesting that Lmp2 deficiency in cardiomyocytes causes this cardiac phenotype. The decline of systolic and diastolic function was accompanied by increased gain in heart weight to body weight ratio as well as wall thickness, ruling out dilatation of the left ventricle. On cellular level, cardiomyocyte cross-sectional area was markedly augmented (+52% vs. +32% Lmp2 KO vs. WT) as compared to corresponding sham-treated mice (p<0.05, n=3) without altering cardiomyocyte length. To exclude an impact of the remodeling process per se on measuring ventricular function, cardiac contractility was directly assessed by using speckle-tracking analyses. Interestingly, peak circumferential strain and strain rate were both markedly decreased in Lmp2 KO mice following isoproterenol treatment as compared to WT mice. Conclusions: Cardiac, presumably cardiomyocyte induction of Lmp2 seems to be protective in the course of cardiac hypertrophy while lack of Lmp2 exacerbates cardiac remodeling, causing a decline of cardiac function despite increased ventricular muscle mass.