Abstract 1424: Enhancement of Hsp22 Induction by Geranylgeranylacetone in Desmin-Related Cardiomyopathy
An arg120gly (R120G) missense mutation in an α-β-crystallin (CryAB), which belongs to the small heat shock protein (HSP) family, causes desmin-related cardiomyopathy (DRM) that is characterized by the formation of aggregates containing the CryAB and desmin. The mutant CryAB protein causes the formation of inclusion bodies, which contain amyloid oligomer intermediates (oligo) in the cardiomyocytes. Although small HSPs, such as HSP25 and HSP22, can directly interrupt the oligo formation caused by the mutant CryAB R120G protein in in vitro, the in vivo protective effects of the small HSPs on the development of DRM is still uncertain. Geranylgeranylacetone (GGA), which is known as a nontoxic antiulcer drug as well as a potent HSP inducer was administered to induce HSPs. Oral administration of GGA resulted not only in up-regulation of the expression level of HSP22 and HSP25 in the heart of CryAB R120G transgenic (R120G TG) mice, but also in reduction of the level of oligo and aggregates in the mice containing the mutant R120G protein. Furthermore, R120G TG mice treated with GGA exhibited decreased heart size, inhibited interstitial fibrosis, improved cardiac function, and recovered survival rate, compared to untreated R120G TG mice. To further address the underlying mechanism(s) for beneficial effects of GGA on the development of DRM linked to the R120G mutation, cardiac-specific transgenic mice expressing HSP22 were generated (HSP22 TG). HSP22 TG mice showed twice the expression level of HSP22 without affecting other small HSP levels of expression. Overexpression of HSP22 led to a reduction in the oligo and aggregate formation, resulting in improvement of the cardiac function and recovery of the survival rate. Treatment with GGA as well as the overexpression of HSP22 also inhibited Cytochrome C release from mitochondria, activation of caspase-3 and TUNEL-positive cardiomyocyte death in the R120G TG mice. Additional expression of small HSPs, such as HSP22, by GGA may be a new therapeutic strategy for patients with DRM as well as other types of amyloid-based degenerative diseases.