Abstract 12922: Cardiac Histone Deacetylase 6 Activity is Critical for Disease Progression in Desmin-Related Cardiomyopathy
Background: An arg120gly (R120G) missense mutation in crystallin, alpha B (CRYAB), a member of the small heat shock protein family, causes desmin-related cardiomyopathy (DRM), which is characterized by the formation of aggresomes containing CRYAB and desmin. Although it is known that small aggregates are retrogradely transported via the microtubule network to form these aggresomes around nuclei, and that these aggresomes are associated with cardiac disease in DRM, the mechanisms underlying the aggresomal formation remain uncertain.
Methods and Results: Aggresomal formation due to mutant CRYAB was analyzed in neonatal rat cardiomyocytes. Overexpression of CRYAB R120G induced by an adenoviral transduction system led to the development of CRAYB-positive aggresomes around nuclei with a concomitant reduction in cell viability in the myocytes. Overexpression of the mutant CRYAB increased acetylated tubulin levels and reduced tubulin deacetylation activity in the myocytes, suggesting that tubulin deacetylating ability is impaired by CRYAB R120G. CRYAB R120G aggresomal formation in cardiomyocytes was dose-dependently enhanced by trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, and was dramatically enhanced in a similar manner by small interfering RNA (siRNA) targeting HDAC6 in cardiomyocytes. Both TSA and siRNA targeting HDAC6 reduced cell viability in the cardiomyocytes expressing CRYAB R120G. These results suggest that a reduction in HDAC6 activity may be involved in the progression of aggresomal formation and cardiac disease in DRM. To confirm the results of the in vitro portion of our study, we examined in vivo research. The administration of valproic acid (VPA), another HDAC inhibitor, resulted in increased tubulin acetylation activity as well as a higher number of CRYAB-positive aggresomes in R120G transgenic (TG) mice hearts. Cardiac-specific TG mice with overexpressed HDAC6 or dominant negative HDAC6 showed similar results as those of the VPA-treated mice. These results indicate that HDAC inhibition exacerbates cardiac disease in mice with DRM.
Conclusion: Impairment of HDAC6 activity may be a critical factor involved in both aggresomal formation and cardiac disease in DRM.
- © 2010 by American Heart Association, Inc.