Abstract P273: Enhancement of Proteasomal Function Protects Against Proteinopathy and Myocardial Ischemia-Reperfusion Injury in Mice

Abstract

The ubiquitin-proteasome system degrades most intracellular proteins, including misfolded proteins. Proteasome functional insufficiency (PFI) was observed in experimental proteinopathies and implicated in many human common diseases but its pathogenic role has not been established because a measure to enhance proteasome function in the cell has not been reported until very recently. We have recently discovered that overexpression of proteasome activator 28α (PA28α) enhances proteasome-mediated removal of abnormal proteins in the cell and protects against oxidative stress in cultured cardiomyocytes ( FASEB J 2011; 25(3):883-93 ). Here we have extended the in vitro discoveries to intact animals. First, we created inducible transgenic mice with cardiomyocyte-restricted PA28α overexpression (CR-PA28αOE). CR-PA28αOE does not alter the homeostasis of normal proteins and cardiac function but increases the degradation of a surrogate misfolded protein in the heart. This marks the establishment of the first animal model of benign enhancement of proteasomal function. Second, by breeding CR-PA28αOE mice with a well-established mouse model of mutant αB-crystallin (CryAB R120G ) based desmin-related cardiomyopathy, a bona fide cardiac proteinopathy, we demonstrate that CR-PA28αOE markedly reduced aberrant protein aggregation and cardiac hypertrophy and the lifespan of the animals significantly increased. Furthermore, PA28α knockdown promoted, while PA28αOE attenuated, CryAB R120G protein accumulation in cultured cardiomyocytes. Finally, we tested the effect of proteasome functional enhancement on myocardial ischemia/reperfusion (I/R) injury induced by ligation and subsequent release of the left anterior descending artery. We found that the infarct size was significantly reduced and cardiac function recovery during reperfusion was markedly facilitated in the CR-PA28αOE mice, compared with their littermate control mice. We conclude that (1) benign enhancement of cardiac proteasome function can be achieved by CR-PA28αOE; (2) PFI plays a major pathogenic role in proteinopathy and myocardial I/R injury; and (3) upregulating PA28α is potentially a novel therapeutic strategy for proteinopathies and disease alike.