Reduced sarcoplasmic calcium ATPase (SERCA2a) expression has been shown to play 
a significant role in the cardiac dysfunction in diabetic cardiomyopathy. The 
mechanism of SERCA2a repression is, however, not known. This study was designed 
to examine the effect of resveratrol (RSV), a potent activator of SIRT1, on 
cardiac function and SERCA2a expression in chronic type 1 diabetes. Adult male 
mice were injected with streptozotocin (STZ) and fed with either a regular diet 
or a diet enriched with RSV. STZ administration produced progressive decline in 
cardiac function, associated with markedly reduced SERCA2a and SIRT1 protein 
levels and increased collagen deposition; RSV treatment to these mice had a 
tremendous beneficial effect both in terms of improving SERCA2a expression and 
on cardiac function. In cultured cardiomyocytes, RSV restored SERCA2 promoter 
activity, which was otherwise highly repressed in high-glucose media. Protective 
effects of RSV were found to be dependent on its ability to activate Silent 
information regulator (SIRT) 1. In cardiomyocytes, overexpression of SIRT1 was 
found sufficient to activate SERCA2 promoter in a dose-dependent manner. In 
contrast, pretreatment of cardiomyocytes with SIRT1 antagonist, splitomycin, 
blocked these beneficial effects of RSV. In addition, SIRT1 knockout (+/-) mice 
were also found to be more sensitive to STZ-induced decline in SERCA2a mRNA. The 
data demonstrate that, in chronic diabetes, 1) the enzymatic activity of cardiac 
SIRT1 is reduced, which contributes to reduced expression of SERCA2a and 2) 
through activation of SIRT1, RSV enhances expression of SERCA2a and improves 
cardiac function.