Several lines of evidence support a role for oxidative stress in
diabetic complications. Diabetic patients have increased O(2)(-) production in monocytes. Loss of
SIRT1 activity may be associated with
metabolic diseases such as diabetes. Several studies have shown that
SIRT1 can regulate mammalian FOXO
transcription factors through direct binding and/or deacetylation. However, interactions between
SIRT1 and FOXO under diabetic conditions are unclear. The
phytochemical resveratrol has recently gained attention for its protection against
metabolic disease.
Resveratrol has been shown to increase mitochondrial function by activating
SIRT1. In this study, we tested the protective effect of
resveratrol on cellular oxidative stress through the SIRT1-FOXO pathway under high-
glucose conditions. Human monocytic (THP-1) cells were cultured in the presence of
mannitol (osmolar control) or normoglycemic (NG, 5.5 mmol/
l glucose) or hyperglycemic (HG, 25 mmol/
l glucose) conditions in absence or presence of
resveratrol (3 and 6 μmol/l) for 48 h. We first examined
SIRT1 activity and oxidative stress in monocytes of
Type 1 diabetes mellitus (T1DM) patients compared with healthy controls. In T1DM patients, monocytic
SIRT1 expression was significantly decreased and p47phox expression was increased compared with controls. Under HG in vitro,
SIRT1 and FOXO3a were significantly decreased compared with NG, and this was reversed by
resveratrol treatment, concomitant with reduction in HG-induced
superoxide production and p47phox. Under HG,
SIRT1 small interfering RNA (
siRNA) inhibited FOXO3a, and there was no beneficial effect of
resveratrol in
siRNA-treated HG-induced cells. Thus,
resveratrol decreases HG-induced
superoxide production via up-regulation of
SIRT1, induction of FOXO3a and inhibition of p47phox in monocytes.