Fig. 2.

SIRT1 activation is a common effect of resveratrol and NAD that may drive beneficial effects in hemorrhagic shock and reperfusion. Resveratrol not only directly activates SIRT1 but may also indirectly activate it by increasing NAD levels via the AMPK pathway. Resveratrol inhibits COX2 leading to reduced platelet aggregation and stimulates the estrogen receptor PI3K/AKT pathway. Activation of this pathway promotes vascular endothelial function, decreases inflammation, and protects against oxidative stress. NAD is required by SIRT1 as well as the other sirtuins (SIRT2–7). NAD also plays essential roles in redox metabolism and is a substrate for CD38 and PARPs. CD38 and PARPs can contribute to inflammation and apoptosis, and by competing for NAD, may reduce SIRT1 activity. SIRT1 acts via multiple downstream pathways that could ameliorate damage in hemorrhagic shock and resuscitation. It inhibits NFκB, in turn inhibiting the expression of multiple downstream pro-inflammatory cytokines. By inhibiting p53, SIRT1 can suppress cellular apoptosis and mitigate mitochondrial dysfunction. SIRT1 activates FOXO3 and PGC1α to increase antioxidant gene expression and increase mitochondrial biogenesis and respiratory activity. SIRT1 also differentially modulates the hypoxia-inducible factors HIF1α and HIF2α, which may favor mitochondrial respiration while promoting erythropoietin expression. Together, these effects are expected to increase cellular ATP levels, preserve vascular endothelial cell function, and ameliorate organ dysfunction