Fidarestat improves cardiomyocyte contractile function in db/db diabetic obese mice through a histone deacetylase Sir2-dependent mechanism.
Avainsanat
Abstrakti
BACKGROUND
Fidarestat, an aldose reductase (AR) inhibitor, displays promise for the treatment of diabetic neuropathy, although the underlying mechanism of action remains unclear. Histone modification, especially histone acetylation, has been implicated in the pathogenesis of diabetes and its complications.
OBJECTIVE
The aim of this study was two-fold: to examine the impact of fidarestat on diabetic cardiomyopathy; and to evaluate the role of histone acetylation in the fidarestat-elicited effect, if any.
METHODS
Cardiomyocytes from db/db diabetic obese and control mice were exposed to fidarestat (0.1-10 mumol/l) for 60 min in the absence or presence of splitomicin, an inhibitor of the NAD-dependent histone deacetylase Sir2. Superoxide levels were measured by dihydroethidium fluorescence. Expression of Sir2, IkappaB (inhibitor of kappaB) and phosphorylated IkappaB was evaluated by western blotting.
RESULTS
Myocytes from db/db mice exhibited greater cross-sectional area, depressed peak shortening and maximal velocity of shortening/re-lengthening, and prolonged duration of re-lengthening (TR90). Myocytes from db/db mice displayed a reduced rise in intracellular Ca and prolonged intracellular Ca decay. All abnormalities were attenuated by fidarestat. The beneficial effects of fidarestat on db/db cardiomyocytes were nullified by splitomicin with the exception of intracellular Ca decay rate and TR90. Intracellular superoxide was enhanced in db/db myocytes, which was attenuated by fidarestat. Protein expression of Sir2 was decreased in db/db mouse hearts. Phosphorylated IkappaB: IkappaB ratio was increased in db/db mouse. Fidarestat reduced the elevated phosphorylated IkappaB: IkappaB ratio, the effect of which was abolished by splitomicin.
CONCLUSIONS
Collectively, these results suggest that fidarestat may protect against cardiomyocyte dysfunction in db/db mice through a Sir2-dependent pathway.
