Sirtuin 2 (
Sirt2) is known to negatively regulate
anoxia-reoxygenation injury in myoblasts. Because
protein levels of
Sirt2 are increased in
ischemia-reperfusion (I/R)-injured liver tissues, we examined whether
Sirt2 is protective or detrimental against hepatic I/R injury. We overexpressed
Sirt2 in the liver of C57BL/6 mice using a
Sirt2 adenovirus. Wild-type and
Sirt2 knockout mice were subjected to a partial (70%) hepatic
ischemia for 45 minutes, followed by various periods of reperfusion. In another set of experiments, wild-type mice were pretreated intraperitoneally with AGK2, a
Sirt2 inhibitor. Isolated hepatocytes and Kupffer cells from wild-type and
Sirt2 knockout mice were subjected to
hypoxia-reoxygenation injury to determine the in vitro effects of
Sirt2. Mice subjected to I/R injury showed typical patterns of hepatocellular damage. Prior injection with
Sirt2 adenovirus aggravated liver injury, as demonstrated by increases in serum
aminotransferases, prothrombin time, proinflammatory
cytokines, hepatocellular
necrosis and apoptosis, and neutrophil infiltration relative to control virus-injected mice. Pretreatment with AGK2 resulted in significant improvements in serum
aminotransferase levels and histopathologic findings. Similarly, experiments with
Sirt2 knockout mice also revealed reduced hepatocellular injury. The molecular mechanism of
Sirt2's involvement in this aggravation of hepatic I/R injury includes the deacetylation and inhibition of
mitogen-activated protein kinase phosphatase-1 and consequent activation of
mitogen-activated protein kinases.
CONCLUSION: