Rescue of Cardiac Function Lost Due to Congenital Defect in Proteasome Heterogeneity

The ubiquitin-proteasome system is a major regulator of protein homeostasis in health and disease by targeted proteolysis. Recent findings show that the heterogeneity of proteasome complexes is dynamically altered via elevated incorporation of non-essential proteasome subunits in the pathogenesis of cardiac remodeling. However, the impact of this regulatory event on cardiac remodeling is not known. Therefore, aim of the study was to determine the influence of the non-essential proteasome subunit Lmp2 on cardiac remodeling induced by chronic catecholamine exposure. Wild-type mice subjected to 30mg/kg isoproterenol for 7 days developed cardiac hypertrophy with increased cardiac function (fractional shortening/FS: +18% vs. pre-treatment). In hearts of these mice, Lmp2 showed increased abundance and incorporation in proteasome complexes. Adult mice lacking Lmp2 congenitally seem phenotypically indistinguishable from wild-types, but developed exacerbated cardiac hypertrophy with decreased cardiac function (FS: -27% vs. wt) upon continuous isoproterenol stimulation. Myocardial transfer of the gene encoding Lmp2 via adeno-associated virus in adult mice resulted in the expression of its processed form comparable to wild-type levels with no obvious phenotypic effects under unstimulated conditions. Upon catecholamine challenge, increasing levels of processed Lmp2 were detected in hypertrophied hearts, suggesting induced functional incorporation in proteasome complexes similar to observations previously made in wild-type animals. Re-expression of Lmp2 reduced the extent of cardiac remodeling in mice congenitally lacking this subunit and rescued cardiac function at least in part (FS: +13% vs. treated virus control). In conclusion, the study demonstrates for the first time that induced expression of the non-essential proteasome subunit Lmp2 is a regulatory mechanism of targeted proteolysis, which mitigates cardiac remodeling and contributes to maintaining cardiac function.